Low hygroscopic aripiprazole drug substance and processes for the preparation thereof

ABSTRACT

The present invention provides low hygroscopic forms of aripiprazole and processes for the preparation thereof which will not convert to a hydrate or lose their original solubility even when a medicinal preparation containing the aripiprazole anhydride crystals is stored for an extended period.

DETAILED DESCRIPTION OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to an improved form of aripiprazolehaving reduced hygroscopicity and processes for the preparation of thisimproved form.

[0003] 2. Background of the Invention

[0004] Aripiprazole,7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril or7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2(1H)-quinolinone,is an atypical antipsychotic agent useful for the treatment ofschizophrenia (U.S. Pat. No. 4,734,416 and U.S. Pat. No. 5,006,528).Schizophrenia is a common type of psychosis characterized by delusions,hallucinations and extensive withdrawal from others. Onset ofschizophrenia typically occurs between the age of 16 and 25 and affects1 in 100 individuals worldwide. It is more prevalent than Alzheimer'sdisease, multiple sclerosis, insulin-dependent diabetes and musculardystrophy. Early diagnosis and treatment can lead to significantlyimproved recovery and outcome. Moreover, early therapeutic interventioncan avert costly hospitalization.

[0005] According to Example 1 of Japanese Unexamined Patent PublicationNo. 191256/1990, aripiprazole anhydride crystals are manufactured forexample by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with1-(2,3-dichlorophenylpiperadine and recrystallizing the resulting rawaripiprazole anhydride with ethanol. Also, according to the Proceedingsof the 4th Japanese-Korean Symposium on Separation Technology (Oct. 6-8,1996), aripiprazole anhydride crystals are manufactured by heatingaripiprazole hydrate at 80° C. However, the aripiprazole anhydridecrystals obtained by the aforementioned methods have the disadvantage ofbeing significantly hygroscopic.

[0006] The hygroscopicity of these crystals makes them difficult tohandle since costly and burdensome measures must be taken in orderensure they are not exposed to moisture during process and formulation.Exposed to moisture, the anhydrous form can take on water and convert toa hydrous form. This presents several disadvantages. First, the hydrousforms of aripiprazole have the disadvantage of being less bioavailableand less dissoluble than the anhydrous forms of aripiprazole. Second,the variation in the amount of hydrous versus anhydrous aripiprazoledrug substance from batch to batch could fail to meet specifications setby drug regulatory agencies. Third, the milling may cause the drugsubstance, Conventional Anhydride, to adhere to manufacturing equipmentwhich may further result in processing delay, increased operatorinvolvement, increased cost, increased maintenance and lower productionyield. Fourth, in addition to problems caused by introduction ofmoisture during the processing of these hygroscopic anhydrides, thepotential for absorbance of moisture during storage and handling wouldadversely affect the dissolubility of aripiprazole drug substance. Thusshelf-life of the product could be significantly decreased and/orpackaging costs could be significantly increased. It would be highlydesirable to discover a form of aripiprazole that possessed lowhygroscopicity thereby facilitating pharmaceutical processing andformulation operations required for producing dosage units of anaripiprazole medicinal product having improved shelf-life, suitabledissolubility and suitable bioavailability.

[0007] Also, Proceedings of the 4th Japanese-Korean Symposium onSeparation Technology (Oct. 6-8, 1996) state that, aripiprazoleanhydride crystals exist as type-I crystals and type-II crystals; thetype-I crystals of aripiprazole anhydride can be prepared byrecrystallizing from an ethanol solution of aripiprazole, or by heatingaripiprazole hydrate at 80° C.; and the type-II crystals of aripiprazoleanhydride can be prepared by heating the type-I crystals of aripiprazoleanhydride at 130 to 140° C. for 15 hours.

[0008] By the aforementioned methods, aripiprazole anhydride type-IIcrystals having high purity can not be easily prepared in an industrialscale with good repeatability.

SUMMARY OF THE INVENTION

[0009] Thus according to the present invention is provided a form ofaripiprazole having reduced hygroscopicity and which is more amenable topharmaceutical processing and formulation. The inventors of the presentinvention have discovered that this reduced-hygroscopic form ofAripiprazole is a crystalline substance defined herein as Anhydride B. Aparticular process for the preparation of this anhydrous crystallinesubstance has also been discovered and comprises yet another aspect ofthe present invention. Particularly, it was discovered as part of thepresent invention that in order to produce Anhydride B having thedesired pharmaceutical properties and utilizing the most efficientprocess, Hydrate A, as defined herein, would have to serve as theintermediate. It was also discovered that a particular sequence ofprocessing had to be implemented in order to form Hydrate A. It wasdiscovered that the preparation of Hydrate A required milling what isdefined herein as Conventional Hydrate. Then, Hydrate A can betransformed into Anhydride B through suitable heating as defined herein.Surprisingly, if the Conventional Hydrate is first heated and thenmilled, serious agglomeration sets in rendering the processingcommercially unsuitable.

[0010] An object of the present invention is to provide novelaripiprazole anhydride crystals.

[0011] Moreover, another object of the present invention is to providearipiprazole anhydride crystals which neither easily convert intohydrates nor substantially decrease the original solubility, even when apharmaceutical composition comprising aripiprazole anhydride is storedfor a long period of time.

[0012] Further object of the present invention is to provide preparationmethods, in order to obtain aripiprazole anhydride crystals having highpurity in an industrial scale with good repeatability.

[0013] The present inventors have conducted research works aimed toattain the aforementioned objects. In the course of the research, theyhave found that the desired aripiprazole anhydride crystals can beobtained when a well-known aripiprazole anhyride is heated at thespecific temperature. Further, the present inventors have found that thedesired aripiprazole anhydride crystals can be obtained fromrecrystallization of a well-known aripiprazole anhydride by using thespecific solvents. Moreover, the present inventors found that thedesired aripiprazole anhydride crystals can be obtained by suspending awell-known aripiprazole anhydride in the specific solvent, and heatingthus obtained suspension.

[0014] The present invention thus completed on the basis of thesefindings and knowledge.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]FIG. 1 is a thermogravimetric/differential thermogram of theAripiprazole Hydrate A obtained in Example 1.

[0016]FIG. 2 shows the ¹H-NMR spectrum (DMSO-d₆, TMS) of theAripiprazole Hydrate A obtained in Example 1.

[0017]FIG. 3 is a powder x-ray diffraction diagram of the AripiprazoleHydrate A obtained in Example 1.

[0018]FIG. 4 shows the ¹H-NMR spectrum (DMSO-d₆, TMS) of theAripiprazole Anhydride Crystals B obtained in Example 2.

[0019]FIG. 5 is a powder x-ray diffraction diagram of the AripiprazoleAnhydride Crystals B obtained in Example 2.

[0020]FIG. 6 is a thermogravimetric/differential thermogram of thearipiprazole hydrate obtained in Reference Example 3.

[0021]FIG. 7 is a powder x-ray diffraction diagram of the aripiprazolehydrate obtained in Reference Example 3.

[0022]FIG. 8 shows thermogravimetric/differential thermal analysisendothermic curve of the type C crystals of aripiprazole anhydrideobtained in Example 11.

[0023]FIG. 9 shows an ¹H-NMR spectrum (DMSO-d₆, TMS) of the type Ccrystals of aripiprazole anhydride obtained in Example 11.

[0024]FIG. 10 shows a powder X-ray diffraction spectrum of the type Ccrystals of aripiprazole anhydride obtained in Example 11.

[0025]FIG. 11 shows an IR spectrum of the type C crystals ofaripiprazole anhydride obtained in Example 11.

[0026]FIG. 12 shows a solid ¹³C-NMR spectrum of the type C crystals ofaripiprazole anhydride obtained in Example 11.

[0027]FIG. 13 shows a thermogravimetric/differential thermal analysisendothermic curve of the type D crystals of aripiprazole anhydrideobtained in Example 12 or Example 13.

[0028]FIG. 14 shows an ¹H-NMR spectrum (DMSO-d₆, TMS) of the type Dcrystals of aripiprazole anhydride obtained in Example 12 or Example 13.

[0029]FIG. 15 shows a powder X-ray diffraction spectrum of the type Dcrystals of aripiprazole anhydride obtained in Example 12 or Example 13.

[0030]FIG. 16 shows an IR spectrum of the type D crystals ofaripiprazole anhydride obtained in Example 12 or Example 13.

[0031]FIG. 17 shows a solid ¹³C-NMR spectrum of the type D crystals ofaripiprazole anhydride obtained in Example 12 or Example 13.

[0032]FIG. 18 shows a thermogravimetric/differential thermal analysisendothermic curve of the type E crystals of aripiprazole anhydrideobtained in Example 14.

[0033]FIG. 19 shows an ¹H-NMR spectrum (DMSO-d₆, TMS) of the type Ecrystals of aripiprazole anhydride obtained in Example 14.

[0034]FIG. 20 shows a powder X-ray diffraction spectrum of the type Ecrystals of aripiprazole anhydride obtained in Example 14.

[0035]FIG. 21 shows an IR spectrum of the type E crystals ofaripiprazole anhydride obtained in Example 14.

[0036]FIG. 22 shows a thermogravimetric/differential thermal analysisendothermic curve of the type F crystals of aripiprazole anhydrideobtained in Example 15.

[0037]FIG. 23 shows an ¹H-NMR spectrum (DMSO-d₆, TMS) of the type Fcrystals of aripiprazole anhydride obtained in Example 15.

[0038]FIG. 24 shows a powder X-ray diffraction spectrum of the type Fcrystals of aripiprazole anhydride obtained in Example 15.

[0039]FIG. 25 shows an IR spectrum of the type F crystals ofaripiprazole anhydride obtained in Example 15.

[0040]FIG. 26 shows thermogravimetric/differential thermal analysisendothermic curve of the type G crystals of aripiprazole anhydrideobtained in Example 16-b).

[0041]FIG. 27 shows an ¹H-NMR spectrum (DMSO-d₆, TMS) of the type Gcrystals of aripiprazole anhydride obtained in Example 16-b).

[0042]FIG. 28 shows a powder X-ray diffraction spectrum of the type Gcrystals of aripiprazole anhydride obtained in Example 16-b).

[0043]FIG. 29 shows an IR spectrum of the type G crystals ofaripiprazole anhydride obtained in Example 16-b).

[0044]FIG. 30 shows a thermogravimetric/differential thermal analysisendothermic curve of the glass form of aripiprazole anhydride obtainedin Example 16-a).

[0045]FIG. 31 shows a powder X-ray diffraction spectrum of the glassystate of aripiprazole anhydride obtained in Example 16-a).

DETAILED DESCRIPTION OF THE INVENTION

[0046] According to first embodiment of the first aspect of the presentinvention is provided Hydrate A of aripiprazole wherein said Hydrate hasa powder x-ray diffraction spectrum which is substantially the same asthe powder x-ray diffraction spectrum shown in FIG. 3.

[0047] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has powder x-ray diffraction characteristic peaks at 2θ=12.6°,15.4°, 17.3°, 18.0°, 18.6°, 22.5° and 24.8°.

[0048] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has particular infrared absorption bands at 2951, 2822, 1692,1577, 1447, 1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr) spectrum.

[0049] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has an ¹H-NMR spectrum which is substantially the same as the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 2.

[0050] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has an ¹H-NMR spectrum (DMSO-d₆, TMS) having characteristicpeaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m,4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm(brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz,1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

[0051] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has an endothermic curve which is substantially the same as thethermogravimetric/differential thermal analysis (heating rate 5° C./min)endothermic curve shown in FIG. 1.

[0052] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has a mean particle size of 50 μm or less.

[0053] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has a mean particle size of 40 μm or less.

[0054] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has a mean particle size of 35 μm or less.

[0055] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has a mean particle size of 30 μm or less.

[0056] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has a mean particle size of 25 μm or less.

[0057] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has a mean particle size of 20 μm or less.

[0058] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has a mean particle size range of 40 to 10 μm.

[0059] According to another embodiment of the first aspect of thepresent invention is provided Hydrate A of aripiprazole wherein saidHydrate has a mean particle size range of 36 to 14 μm.

[0060] According to a second aspect of the present invention is provideda process for the preparation of Hydrate A wherein said processcomprises the steps of milling Conventional Hydrate.

[0061] According to a first embodiment of the second aspect of thepresent invention is provided a process for the preparation of Hydrate Acomprising the steps of milling Conventional Hydrate wherein saidmilling is performed by a milling machine.

[0062] According to another embodiment of the second aspect of thepresent invention is provided a process for the preparation of Hydrate Acomprising the steps of milling Conventional Hydrate wherein saidmilling machine is an atomizer, pin mill, jet mill or ball mill.

[0063] According to another embodiment of the second aspect of thepresent invention is provided a process for the preparation of Hydrate Acomprising the steps of milling Conventional Hydrate wherein saidmilling machine is an atomizer.

[0064] According to another embodiment of the second aspect of thepresent invention is provided a process for the preparation of Hydrate Acomprising the steps of milling Conventional Hydrate wherein saidmilling machine is an atomizer using a rotational speed of 5000-15000rpm for the main axis, a feed rotation of 10-30 rpm and a screen holesize of 1-5 mm.

[0065] According to various embodiments of a third aspect of the presentinvention is provided Hydrate A defined according to one or more of theembodiments described herein wherein said Hydrate is made by a processas described herein.

[0066] According to a fourth aspect of the present invention is providedaripiprazole drug substance of low hygroscopicity.

[0067] According to a first embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said low hygroscopicity is a moisture content of0.5% or less after placing said drug substance for 24 hours in adessicator maintained at a temperature of 60° C. and a humidity level of100%.

[0068] According to a first embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said low hygroscopicity is a moisture content of0.4% or less after placing said drug substance for 24 hours in adessicator maintained at a temperature of 60° C. and a humidity level of100%.

[0069] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said low hygroscopicity is a moisture content of0.25% or less after placing said drug substance for 24 hours in adessicator maintained at a temperature of 60° C. and a humidity level of100%.

[0070] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said low hygroscopicity is a moisture content of0.15% or less after placing said drug substance for 24 hours in adessicator maintained at a temperature of 60° C. and a humidity level of100%.

[0071] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said low hygroscopicity is a moisture content of0.10% or less after placing said drug substance for 24 hours in adessicator maintained at a temperature of 60° C. and a humidity level of100%.

[0072] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said low hygroscopicity is a moisture content of0.05% or less after placing said drug substance for 24 hours in adessicator maintained at a temperature of 60° C. and a humidity level of100%.

[0073] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said low hygroscopicity is a moisture content of0.04% or less after placing said drug substance for 24 hours in adessicator maintained at a temperature of 60° C. and a humidity level of100%.

[0074] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance is Aripiprazole AnhydrideCrystals B as defined herein.

[0075] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance has a powder x-raydiffraction spectrum which is substantially the same as the powder x-raydiffraction spectrum shown in FIG. 5.

[0076] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance has a powder x-raydiffraction spectrum having characteristic peaks at 2θ=11.0°, 16.6°,19.3°, 20.3° and 22.1°.

[0077] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance has particular infraredabsorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and779 cm⁻¹ on the IR (KBr) spectrum.

[0078] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance has an ¹H-NMR spectrum whichis substantially the same as the ¹H-NMR spectrum (DMSO-d₆, TMS) shown inFIG. 4.

[0079] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance has an ¹H-NMR spectrum(DMSO-d₆, TMS) having characteristic peaks at 1.55-1.63 ppm (m, 2H),1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

[0080] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance exhibits an endothermic peaknear about 141.5° C. in thermogravimetric/differential thermal analysis(heating rate 5° C./min).

[0081] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance exhibits an endothermic peaknear about 140.7° C. in differential scanning calorimetry (heating rate5° C./min).

[0082] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance is Aripiprazole AnhydrideCrystals B and will not substantially convert to a hydrous form ofaripiprazole when properly stored even for an extended period. Forinstance, said Aripiprazole Anhydride Crystals B can be stored under arelative humidity (RH) of 60% and at a temperature of 25° C., even for aperiod not less than 1 year.

[0083] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance is Aripiprazole AnhydrideCrystals B and will not substantially convert to a hydrous form ofaripiprazole when properly stored even for an extended period. Forinstance, said Aripiprazole Anhydride Crystals B can be stored under arelative humidity (RH) of 60% and at a temperature of 25° C., even for aperiod not less than 4 years.

[0084] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance is Aripiprazole AnhydrideCrystals B and will not substantially convert to a hydrous form ofaripiprazole when properly stored even for a period not less than 0.5year under a relative humidity (RH) of 75% and at a temperature of 40°C.

[0085] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance has a mean size of 50 μm orless when small particle size is required for the formulation such asTablet and other solid dose formulations including for example flashmeltformulations.

[0086] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance has a mean size of 40 μm orless if small particle size is required for the formulation such asTablet and other solid dose formulations including for example flashmeltformulations.

[0087] According to another embodiment of the fourth aspect of thepresent invention is provided aripiprazole drug substance of lowhygroscopicity wherein said drug substance has a mean size of 30 μm orless if small particle size is required for formulation such as Tabletand other solid dose formulations including for example flashmeltformulations.

[0088] According to a fifth aspect of the present invention is provideda process for the preparation of Aripiprazole Anhydride Crystals B.

[0089] According to a first embodiment of the fifth aspect of thepresent invention is provided a process for the preparation ofAripiprazole Anhydride Crystals B wherein said process comprises heatingAripiprazole Hydrate A.

[0090] According to a first embodiment of the fifth aspect of thepresent invention is provided a process for the preparation ofAripiprazole Anhydride Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 90-125° C. for about 3-50 hours.

[0091] According to another embodiment of the fifth aspect of thepresent invention is provided a process for the preparation ofAripiprazole Anhydride Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 100° C. for about 18 hours.

[0092] According to another embodiment of the fifth aspect of thepresent invention is provided a process for the preparation ofAripiprazole Anhydride Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 100° C. for about 24 hours.

[0093] According to another embodiment of the fifth aspect of thepresent invention is provided a process for the preparation ofAripiprazole Anhydride Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 120° C. for about 3 hours.

[0094] According to another embodiment of the fifth aspect of thepresent invention is provided a process for the preparation ofAripiprazole Anhydride Crystals B wherein said process comprises heatingAripiprazole Hydrate A for about 18 hours at 100° C. followed byadditional heating for about 3 hours at 120° C.

[0095] According to a sixth aspect of the present invention is providedAripiprazole Anhydride Crystals B defined according to one or more ofthe embodiments described herein and made by a process as providedherein.

[0096] According to a seventh aspect of the present invention isprovided Aripiprazole Anhydride Crystals B formulated with one or morepharmaceutically acceptable carriers.

[0097] Other embodiments of the present invention may comprise suitablecombinations of two or more of the embodiments and/or aspects disclosedherein.

[0098] Yet other embodiments and aspects of the invention will beapparent according to the description provided below.

[0099] Yet another aspect of the present invention comprised discoveringthat when aripiprazole hydrate (Conventional Hydrate as defined herein)is milled, it converts to an aripiprazole hydrate (Hydrate A as definedherein) with a different powder x-ray diffraction spectrum by differentpeak intensities. Moreover, it was found that Hydrate A loses the sharpdehydration endothermic peak of 123.5° C. which characterizes unmilledConventional Hydrate in thermogravimetric/differential thermal analysis.Thus, the Conventional Hydrate is transformed into Hydrate A aftermilling Conventional Hydrate and exhibits a gradual dehydrationendothermic peak between about 60° C. and 120° C. with a weak peak atabout 71° C.

[0100] Yet another aspect of the invention comprised discovering thatwhen heated to a specific temperature of 90-125° C. for 3-50 hr, thisnovel aripiprazole hydrate dehydrates gradually avoiding the aggregationphenomenon thought to be caused in conventional aripiprazole hydrate byrapid dehydration, and that aripiprazole anhydride crystals obtained byheating of the novel aripiprazole hydrate to a specific temperature arearipiprazole anhydride crystals with the desired properties.

[0101] Characterization of Hydrate A

[0102] Particles of “Hydrate A” as used herein have the physicochemicalproperties given in (1)-(5) below:

[0103] (1) It has an endothermic curve which is substantially the sameas the thermogravimetric/differential thermal analysis (heating rate 5°C./min) endothermic curve shown in FIG. 1. Specifically, it ischaracterized by the appearance of a small peak at about 71° C. and agradual endothermic peak around 60° C. to 120° C.

[0104] (2) It has an ¹H-NMR spectrum which is substantially the same asthe ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 2. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

[0105] (3) It has a powder x-ray diffraction spectrum which issubstantially the same as the powder x-ray diffraction spectrum shown inFIG. 3. Specifically, it has characteristic peaks at 2θ=12.6°, 15.4°,17.3°, 18.0°, 18.6°, 22.5° and 24.8°.

[0106] (4) It has clear infrared absorption bands at 2951, 2822, 1692,1577, 1447, 1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr) spectrum.

[0107] (5) It has a mean particle size of 50 μm or less.

[0108] Process for Manufacturing Hydrate A

[0109] Hydrate A is manufactured by milling Conventional Hydrate.Conventional milling methods can be used to mill Conventional Hydrate.For example, Conventional Hydrate can be milled in a milling machine. Awidely used milling machine can be used, such as an atomizer, pin mill,jet mill or ball mill. Of these, the atomizer is preferred.

[0110] Regarding the specific milling conditions when using an atomizer,a rotational speed of 5000-15000 rpm could be used for the main axis,for example, with a feed rotation of 10-30 rpm and a screen hole size of1-5 mm.

[0111] The mean particle size of the Aripiprazole Hydrate A obtained bymilling should normally be 50 μm or less, preferably 30 μm or less. Meanparticle size can be ascertained by the particle size measurement methoddescribed hereinafter.

[0112] Characterization of Aripiprazole Anhydride Crystals B

[0113] “Aripiprazole Anhydride Crystals B” of the present invention asused herein have the physicochemical properties given in (6)-(12) below.

[0114] (6) They have an ¹H-NMR spectrum which is substantially the sameas the ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 4. Specifically,they have characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm(m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t,J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H),6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

[0115] (7) They have a powder x-ray diffraction spectrum which issubstantially the same as the powder x-ray diffraction spectrum shown inFIG. 5. Specifically, they have characteristic peaks at 2θ=11.0°, 16.6°,19.3°, 20.3° and 22.1°.

[0116] (8) They have clear infrared absorption bands at 2945, 2812,1678, 1627, 1448, 1377, 1173, 960 and 779 cm⁻¹ on the IR (KBr) spectrum.

[0117] (9) They exhibit an endothermic peak near about 141.5° C. inthermogravimetric/differential thermal analysis (heating rate 5°C./min).

[0118] (10) They exhibit an endothermic peak near about 140.7° C. indifferential scanning calorimetry (heating rate 5° C./min).

[0119] (11) Aripiprazole Anhydride Crystals B of the present inventionhave low hygroscopicity. For example, Aripiprazole Anhydride Crystals Bof the present invention maintain a water content of 0.4% or less after24 hours inside a dessicator set at a temperature of 60° C. and ahumidity of 100%. Well-known methods of measuring water content can beused as long as they are methods commonly used for measuring the watercontent of crystals. For example, a method such as the Karl Fischermethod can be used.

[0120] (12) When the small particle size is required for the formulationsuch as tablet and other solid dose formulations including for exampleflashmelt formulations, the mean particle size is preferably 50 μm orless.

[0121] Process for Manufacturing Anhydride B

[0122] In case of the formulation for which small particle size (lessthan 50 μm) is required, the milling is necessary for the preparation.However, when a large amount of Conventional Aripiprazole Anhydride orAnhydride Crystals B having large particle size is milled, the milledsubstances adhere with each other in the milling machine. Accordingly,there is a disadvantage that it is difficult to industrially prepareAripiprazole Anhydride Crystals B having small particle size.

[0123] Under the circumstances, the inventors of the present inventionhave found that Conventional hydrate can be easily milled, andAripiprazole Anhydride B having small particle size can be obtained inhigh yield with good-operability by heating the milled hydrate A thusobtained.

[0124] The Aripiprazole Anhydride Crystals B of the present inventionare prepared for example by heating the aforementioned AripiprazoleHydrate A at 90-125° C. The heating time is generally about 3-50 hours,but cannot be stated unconditionally since it differs depending onheating temperature. The heating time and heating temperature areinversely related, so that for example the heating time will be longerthe lower the heating temperature, and shorter the higher the heatingtemperature. Specifically, if the heating temperature of AripiprazoleHydrate A is 100° C., the heating time should normally be 18 hours ormore or preferably about 24 hours. If the heating temperature ofAripiprazole Hydrate A is 120° C., on the other hand, the heating timecan be about 3 hours. The Aripiprazole Anhydride Crystals B of thepresent invention can be prepared with certainty by heating AripiprazoleHydrate A for about 18 hours at 100° C., and then heating it for about 3hours at 120° C. The Aripiprazole Anhydride Crystals B of the presentinvention can also be obtained if the heating time is extended stillfurther, but this may not be economical.

[0125] When small particle size is not required for the formulation,e.g., when drug substance is being manufactured for injectable or oralsolution formulations, Aripiprazole Anhydride Crystal B can be alsoobtained the following process.

[0126] The inventors also discovered that it is possible to obtainaripiprazole anhydride crystals by heating conventional aripiprazolehydrate or conventional aripiprazole anhydride crystals to a specifictemperature but this process does not yield Anhydride B crystallinesubstance suitable for commercial use in the formulation of solid oraldose formulations.

[0127] Furthermore, the Aripiprazole Anhydride Crystals B of the presentinvention are prepared for example by heating conventional aripiprazoleanhydride crystals at 90-125° C. The heating time is generally about3-50 hours, but cannot be stated unconditionally since it differsdepending on heating temperature. The heating time and heatingtemperature are inversely related, so that for example the heating timewill be longer the lower the heating temperature, and shorter the higherthe heating temperature.

[0128] Specifically, if the heating temperature of the aripiprazoleanhydride crystals is 100° C., the heating time can be about 4 hours,and if the heating temperature is 120° C. the heating time can be about3 hours.

[0129] In addition to Aripiprazole Hydrate A and Aripiprazole AnhydrideCrystals B mentioned above, the present invention provides AripiprazoleAnhydride Crystals C to G as follows.

[0130] 1. The present invention relates to aripiprazole anhydridecrystals (hereinafter referred to as “type C crystals of aripiprazoleanhydride”) having the following physicochemical properties (1) to (5):

[0131] (1) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 8;

[0132] (2) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 9;

[0133] (3) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 10;

[0134] (4) an IR spectrum which is substantially identical to the IR(KBr) shown in FIG. 11; and

[0135] (5) a solid ¹³C-NMR spectrum which is substantially identical tothe solid ¹³C-NMR spectrum shown in FIG. 12.

[0136] 2. The present invention relates to aripiprazole anhydridecrystals (hereinafter referred to as “type D crystals of aripiprazoleanhydride”) having the following physicochemical properties (6) to (10):

[0137] (6) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 13;

[0138] (7) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 14;

[0139] (8) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 15;

[0140] (9) an IR spectrum which is substantially identical to the IR(KBr) shown in FIG. 16; and

[0141] (10) a solid ¹³C-NMR spectrum which is substantially identical tothe ¹³C-NMR spectrum shown in FIG. 17.

[0142] 3. The present invention relates to aripiprazole anhydridecrystals (hereinafter referred to as “type E crystals of aripiprazoleanhydride”) having the following physicochemical properties (11) to(14):

[0143] (11) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 18;

[0144] (12) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 19;

[0145] (13) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 20; and

[0146] (14) an IR spectrum which is substantially identical to the IR(KBr) shown in FIG. 21.

[0147] 4. The present invention relates to aripiprazole anhydridecrystals (hereinafter referred to as “type F crystals of aripiprazoleanhydride”) having the following physicochemical properties (15) to(18):

[0148] (15) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 22;

[0149] (16) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 23;

[0150] (17) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 24; and

[0151] (18) an IR spectrum which is substantially identical to the IR(KBr) shown in FIG. 25.

[0152] 5. The present invention relates a process for preparingaripiprazole anhydride crystals stated in the aforementioned item 1,characterized by heating aripiprazole anhydride crystals at atemperature being higher than 140° C. and lower than 150° C.

[0153] 6. The present invention relates a process for preparingaripiprazole anhydride crystals stated in the aforementioned item 2,characterized by recrystallizing from toluene.

[0154] 7. The present invention relates to a process for preparingaripiprazole anhydride crystals stated in the aforementioned item 3,characterized by heating and dissolving aripiprazole anhydride crystalsin acetonitrile, and cooling it.

[0155] 8. The present invention relates to a process for preparingaripiprazole anhydride crystals stated in the aforementioned item 4,characterized by heating a suspension of aripiprazole anhydride crystalsin acetone.

[0156] 9. The present invention relates to a pharmaceutical compositioncontaining at least one aripiprazole anhydride crystals selected fromthe group consisting of the aripiprazole anhydride crystals stated inthe aforementioned item 1, the aripiprazole anhydride crystals stated inthe aforementioned item 2, the aripiprazole anhydride crystals stated inthe aforementioned item 3, the aripiprazole anhydride crystals stated inthe aforementioned item 4, and the aripiprazole anhydride crystalsstated in the after-mentioned item 10, together with pharmaceuticallyacceptable carriers.

[0157] 10. The present invention relates to aripiprazole anhydridecrystals (hereinafter referred to as “type G crystals of aripiprazoleanhydride”) having the following physicochemical properties (19) to(22):

[0158] (19) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate; 5°C./min.) endothermic curve shown FIG. 26.

[0159] (20) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 27.

[0160] (21) a power X-ray diffraction spectrum which is substantiallyidentical to the power X-ray diffraction spectrum shown in FIG. 28; and

[0161] (22) an IR spectrum which is substnatially identical to the IR(Kbr) shown in FIG. 29.

[0162] 11. The present invention relates to a process for preparingaripiprazole anhydride crystals stated in the aforementioned item 10,characterized by putting glassy state of Aripiprazole Anhydride in asealed vessel and keeping it at room temperature for at least 2 weeks.

[0163] 12. The present invention relates to a process for thepreparation of granules, characterized by wet granulating conventionalAripiprazole Anhydride Crystals or Aripiprazole Anhydride Crystals B, C,D, E, F or G, drying the obtained granules at 70 to 100° C. and sizingit, then drying the sized granules at 70 to 100° C. again.

[0164] 13. The present invention relates to a process for thepharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising conventionalAripiprazole Anhydride Crystals or Aripiprazole Anhydride Crystals B, C,D, E, F or G, and one or more pharmaceutically acceptable carriers at 70to 100° C.

[0165] 14. The present invention relates to a pharmaceutical solid oralpreparation comprising Aripiprazole Anhydride Crystals B, C, D, E, F orG and one or more pharmaceutically acceptable carriers, wherein saidpharmaceutical solid oral preparation has at least one dissolution rateselected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

[0166] 15. The present invention relates to a pharmaceutical solid oralpreparation having at least one dissolution rate selected from the groupconsisting 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.

[0167] 16. The present invention relates to a pharmaceutical solid oralpreparation obtained by wet granulating conventional AripiprazoleAnhydride Crystals, drying the obtained granules at 70 to 100° C. andsizing it, then drying the sized granules at 70 to 100° C. again, andthe pharmaceutical solid oral preparation has at least one dissolutionrate selected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

[0168] 17. The present invention relates to a pharmaceutical solid oralpreparation obtained by drying a pharmaceutical solid oral preparationcomprising conventional Aripiprazole Anhydride Crystals and one or morepharmaceutically acceptable carriers at 70 to 100° C., and thepharmaceutical solid oral preparation has at least one dissolution rateselected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

[0169] 18. The present invention relates to a process for thepreparation of granules, characterized by wet granulating conventionalAripiprazole Hydrate Crystals, drying the obtained granules at 70 to100° C. and sizing it, then drying the sized granules at 70 to 100° C.again.

[0170] 19. The present invention relates to a process for thepharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising conventionalAripiprazole Hydrate Crystals and one or more pharmaceuticallyacceptable carriers at 70 to 100° C.

[0171] 20. The present invention relates to a pharmaceutical solid oralpreparation obtained by wet granulating conventional AripiprazoleHydrate Crystals, drying the obtained granules at 70 to 100° C. andsizing it, then drying the sized granules at 70 to 100° C. again, andthe pharmaceutical solid oral preparation has at least one dissolutionrate selected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

[0172] 21. The present invention relates to a pharmaceutical solid oralpreparation obtained by drying a pharmaceutical solid oral preparationcomprising conventional Aripiprazole Hydrate Crystals and one or morepharmaceutically acceptable carriers at 70 to 100° C., and thepharmaceutical solid oral preparation has at least one dissolution rateselected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.

[0173] The Type C to F crystals of aripiprazole anhydride of the presentinvention correspond to the Type-III to VI crystals of aripiprazoleanhydride disclosed in JP-2001-348276.

[0174] Type C Crystals of Aripiprazole Anhydride

[0175] Type C crystals of aripiprazole anhydride of the presentinvention have the following physicochemical properties (1) to (5):

[0176] (1) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 8, more particularly, it has anendothermic peak around 150.2° C.;

[0177] (2) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 9. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7, 4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H);

[0178] (3) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 10.Specifically, it has characteristic peaks at 2θ=12.6°, 13.7°, 15.4°,18.1°, 19.0°, 20.6°, 23.5° and 26.4°;

[0179] (4) an IR spectrum which is substantially identical to the IR(KBr) spectrum shown in FIG. 11. Specifically, it has clear infraredabsorption bands at 2939, 2804, 1680, 1375 and 780 cm⁻¹; and

[0180] (5) a solid ¹³C-NMR spectrum which is substantially identical tothe solid ¹³C-NMR spectrum shown in FIG. 12, specifically, it hascharacteristic peaks at 32.8 ppm, 60.8 ppm, 74.9 ppm, 104.9 ppm, 152.2ppm, 159.9 ppm and 175.2 ppm.

[0181] Preparation Method of Type C Crystals of Aripiprazole Anhydride

[0182] Type C crystals of aripiprazole anhydride of the presentinvention is prepared, for example by heating an aripiprazole anhydrideat a temperature of higher than 140° C. and lower than 150° C.

[0183] Aripiprazole anhydride used as the raw material may beconventional aripiprazole anhydride crystals, for example, type-Icrystals of aripiprazole anhydride, type-II crystals of aripiprazoleanhydride crystals and the like, and these anhydrides may be eitherpurified products or crude materials. Alternatively, type B crystals ofaripiprazole anhydride, type D crystals of aripiprazole anhydride, typeE crystals of aripiprazole anhydride, type F crystals of aripiprazoleanhydride, or type G crystals of aripiprazole anhydride being preparedin the present invention can be used as the raw material of aripiprazoleanhydrides. These aripiprazole anhydrides can be used singly or incombination of at least 2 kinds thereof.

[0184] Heating temperature is generally higher than 140° C. and lowerthan 150° C., preferably at 142-148° C., and heating time is generallyfor 15 minutes to 3 hours, preferably for 30 minutes to 1 hour.

[0185] When, an aripiprazole anhydride is heated at the above-mentionedtemperature, then type C crystals of aripiprazole anhydride are formed.

[0186] Thus obtained type C crystals of aripiprazole anhydride can beisolated and purified by well-known methods. For example, after heatingthe aripiprazole anhydride at the above-mentioned temperature, and bycooling to a room temperature, then type C crystals of aripiprazoleanhydride, having 100% of purity can be obtained.

[0187] Type D Crystals of Aripiprazole Anhydride

[0188] Type D crystals of aripiprazole anhydride of the presentinvention have the following physicochemical properties (6) to (10):

[0189] (6) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 13; more particularly, it hasan endothermic peak around 136.8° C. and 141.6° C.;

[0190] (7) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 14. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7, 4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H);

[0191] (8) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 15.Specifically, it has characteristic peaks at 2θ=8.7°, 11.6°, 16.3°,17.7°, 18.6°, 20.3°, 23.4° and 25.0°;

[0192] (9) an IR spectrum which is substantially identical to the IR(KBr) spectrum shown in FIG. 16. Specifically, it has clear infraredabsorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm⁻¹; and

[0193] (10) a solid ¹³C-NMR spectrum which is substantially identical tothe solid ¹³C-NMR spectrum shown in FIG. 17, specifically, it hascharacteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4ppm, 158.4 ppm, and 174.1 ppm.

[0194] Preparation Method of Type D Crystals of Aripiprazole Anhydride

[0195] Type D crystals of aripiprazole anhydride of the presentinvention is prepared, for example, by recrystallization of aripiprazoleanhydride from toluene. Specifically, an aripiprazole anhydride is addedto toluene, further heated and dissolved, then thus obtained solution iscooled. By such procedures, type D crystals of aripiprazole anhydride ofthe present invention is separated out as crystals in toluene.

[0196] Aripiprazole anhydride to be used as the raw materials may beconventional aripiprazole anhydride, for example type-I crystals ofaripiprazole anhydride, type-II crystals of aripiprazole anhydride andthe like, and these anhydrides may be either purified products or crudematerials. Alternatively, type B crystals of aripiprazole anhydride,type C crystals of aripiprazole anhydride, type E crystals ofaripiprazole anhydride, type F crystals of aripiprazole anhydride, ortype G crystals of aripiprazole anhydride being prepared in the presentinvention can be used as the raw material for aripiprazole anhydrides.These aripiprazole anhydrides can be used singly or in combination of atleast 2 kinds thereof.

[0197] When the solution obtained by heating and dissolving is cooled,type D crystals of aripiprazole may be added as a seed crystal to saidsolution. Further, the seed crystal may be formed by cooling graduallysaid solution being obtained by heating and dissolving. In the presenceof the seed crystal, type D crystals of aripiprazole anhydride may beseparated out.

[0198] Thus separated out type D crystals of aripiprazole anhydride canbe isolated and purified in accordance with well-known methods. By suchprocedures, type D crystals of aripiprazole anhydride, having the purityof 100% can be obtained.

[0199] Type E Crystals of Aripiprazole Anhydride

[0200] Type E crystals of aripiprazole anhydride of the presentinvention have the following physicochemical properties (11) to (14):

[0201] (11) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 18, specifically, it has anendothermic peak around 146.5° C.;

[0202] (12) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 19. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7, 4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00ppm (s, 1H);

[0203] (13) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 20.Specifically, it has characteristic peaks at 2θ=8.0°, 13.7°, 14.6°,17.6°, 22.5° and 24.0°; and

[0204] (14) an IR spectrum which is substantially identical to the IR(KBr) spectrum shown in FIG. 21. Specifically, it has clear infraredabsorption bands at 2943, 2817, 1686, 1377, 1202, 969 and 774 cm⁻¹.

[0205] Preparation Method of Type E Crystals of Aripiprapzole Anhydride

[0206] Type E crystals of aripiprazole anhydride of the presentinvention is prepared, for example by recrystallization of thearipiprazole anhydride from acetonitrile. Specifically, by adding awell-known aripiprazole anhydride to acetonitrile, heating anddissolving, then the solution thus obtained may be cooled. In accordancewith such procedures, type E crystals of aripiprazole anhydride of thepresent invention are separated out in the acetonitrile.

[0207] When a conventional aripiprazole anhydride is added toacetonitrile, type-I crystals of aripiprazole anhydride, type-IIcrystals of aripiprazole anhydride and type D crystals of aripiprazoleanhydride are separated out, other than type E crystals of aripiprazoleanhydride. Plate crystals being separated out from the acetonitrilesolution at 70° C. are type-I crystals, type-II crystals and type Dcrystals, while type E crystals are precipitated out as needle crystals.When the acetonitrile solution after separated out of these crystals isheated again (for example, heated at over 75° C.), the plate crystals(type-I crystals, type-II crystals and type D crystals) are quicklydissolved, on the contrary, the needle form crystals (type E crystals)do not dissolved. Additionally, when the acetonitrile solution is cooledagain, then needle form crystals (type E crystals) are further separatedout around the needle form crystals (type E crystals) previouslyprecipitated as the seed crystals. Thus, type E crystals of aripiprazoleanhydride can be precipitated in the acetonitrile solution.

[0208] Aripiprazole anhydrides used as the raw materials may beconventional aripiprazole anhydrides, for example any one of type-Icrystals of aripiprazole anhydride and type-II crystals of aripiprazoleanhydride and the like, and these anhydrides may be either purifiedproducts or crude materials. Alternatively, type B crystals ofaripiprazole anhydride, type C crystals of aripiprazole anhydride, typeD crystals of aripiprazole anhydride, type F crystals of aripiprazoleanhydride, or type G crystals of aripiprazole anhydride can be used asthe raw materials for aripiprazole anhydrides. These aripiprazoleanhydrides can be used singly or in combination of at least 2 kindsthereof.

[0209] When the acetonitrile solution obtained by heating (heating anddissolving) is cooled, the type E crystals of aripiprazole may be addedas a seed crystal to said solution. Further, the seed crystal may beformed by cooling gradually said acetonitrile solution which wasobtained by heating.

[0210] Thus separated out type E crystals of aripiprazole anhydride canbe isolated and purified in accordance with well-known methods. By suchprocedures, type E crystals of aripiprazole anhydride, having the purityof 100% can be obtained.

[0211] Type F Crystals of Aripiprazole Anhydride

[0212] Type F crystals of aripiprazole anhydride of the presentinvention have the following physicochemical properties (15) to (18):

[0213] (15) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 22, specifically, it has anendothermic peaks around 137.5° C. and 149.8° C.;

[0214] (16) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 23. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7, 4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H);

[0215] (17) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 24.Specifically, it has characteristic peaks 2θ=11.3°, 13.3°, 15.4°, 22.8°,25.2° and 26.9°, and

[0216] (18) Having an IR spectrum which is substantially identical tothe IR (KBr) spectrum shown in FIG. 25. Specifically, it has clearinfrared absorption bands at 2940, 2815, 1679, 1383, 1273, 1177, 1035,963 and 790 cm⁻¹.

[0217] Preparation Method of Type F Crystals of Aripiprazole Anhydride

[0218] Type F crystals of aripiprazole anhydride of the presentinvention is prepared, for example by suspending an aripiprazoleanhydride in acetone, and thus obtained acetone suspension is heated.

[0219] Aripiprazole anhydrides used as the raw materials may beconventional aripiprazole anhydride, for example any one of type-Icrystals of aripiprazole anhydride and type-II crystals of aripiprazoleanhydride and the like, and these anhydrides may be either purifiedproducts or crude materials. Alternatively, type B crystals ofaripiprazole anhydride, type C crystals of aripiprazole anhydride, typeD crystals of aripiprazole anhydride, type E crystals of aripiprazoleanhydride, or type G crystals of aripiprazole anhydride prepared in thepresent invention can be used as the raw materials for aripiprazoleanhydrides. These aripiprazole anhydrides can be used singly or incombination of at least 2 kinds thereof.

[0220] Heating temperature of the acetone suspension may be generallyabout the boiling point of acetone, and heating time is generally 5 to10 hours. When the acetone suspension is heated about the boiling pointof acetone, then type F crystals of aripiprazole anhydride is formed,the crystals are isolated by filtration with heating. Isolation of thecrystals may be carried out in accordance with well-known methods. Bysuch procedures, type F crystals of aripiprazole anhydride, having thepurity of 100% can be obtained.

[0221] Type G Crystals of Aripiprazole Anhydride

[0222] Type G crystals of aripiprazole anhydride of the presentinvention have the following physicochemical properties (19) to (22):

[0223] (19) an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 26, more particularly, it hasan endothermic peak around 141.0° C. and an exothermic peak around122.7° C.;

[0224] (20) an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 27. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.49 ppm(dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm(m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H);

[0225] (21) a powder X-ray diffraction spectrum which is substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 28.Specifically, it has characteristic peaks 2θ=10.1°, 12.8+, 15.2°, 17.0°,17.5°, 19.1°, 20.1°, 21.2°, 22.4°, 23.3°, 24.5° and 25.8°; and

[0226] (22) an IR spectrum which is substantially identical to the IR(KBr) spectrum shown in FIG. 29. Specifically, it has clear infraredabsorption bands at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787cm⁻¹.

[0227] Preparation Method of Type G Crystals of Aripiprazole Anhydride

[0228] Type G crystals of aripiprazole anhydride of the presentinvention can be prepared, for example by putting glassy state ofaripiprazole anhydride in a sealed vessel and leaving to stand it atroom temperature for at least two weeks, preferably two weeks to sixmonths. Further, glassy state of aripiprazole anhydride as startingmaterial can be obtained by heating and melting aripiprazole anhydrideat around 170° C., then cooling it to room temperature.

[0229] Aripiprazole anhydride used as the raw material may be well-knownaripiprazole anhydride crystals, for example, any one of type-I crystalsof aripiprazole anhydride and type-II crystals of aripiprazole anhydrideand the like, and these anhydrides may be either purified products orcrude materials. Alternatively, type B crystals of aripiprazoleanhydride, type C crystals of aripiprazole anhydride, type D crystals ofaripiprazole anhydride, type E crystals of aripiprazole anhydride, ortype F crystals of aripiprazole anhydride being prepared in the presentinvention can be used as the raw material of aripiprazole anhydrides.These aripiprazole anhydrides can be used singly or in combination of atleast 2 kinds thereof.

[0230] Thus obtained type G crystals of aripiprazole anhydride can beisolated and purified by well-known methods. For example, glassy stateof aripiprazole anhydride leave to stand according to theabove-mentioned method, then type G crystals of aripiprazole anhydride,having 100% of purity can be obtained.

[0231] Type C crystals of aripiprazole anhydride, type D crystals ofaripiprazole anhydride, type E crystals of aripiprazole anhydride, typeF crystals of aripiprazole anhydride and type G crystals of aripiprazoleanhydride of the present invention neither easily convert into hydratesthereof, nor substantially decrease the original solubility, even whenthey are stored for a long period of time.

[0232] In accordance with the present invention, methods for preparingaripiprazole anhydride crystals having high purity, which can apply inan industrial scale with a good repeatability is provided.

[0233] In accordance with the present invention, pharmaceuticalcompositions comprising aripiprazole anhydride crystals are provided, ofwhich the solubility does not decrease, and of which the stability cankeep excellent, even if they are stored for long time.

[0234] The aripiprazole anhydride crystals which are the raw materialfor preparing the Aripiprazole Anhydride Crystals B to G of the presentinvention are prepared for example by Method a or b below.

[0235] “Method a”: Process for Preparing Crude Aripiprazole Crystals

[0236] Conventional Aripiprazole Anhydride crystals are prepared bywell-known methods, as described in Example 1 of Japanese UnexaminedPatent Publication No. 191256/1990.

[0237] A suspension of 47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril,35 g of sodium iodide with 600 ml of acetonitrile was refluxed for 30minutes. To this suspension was added 40 g of1-(2,3-dichlorophenyl)piperazine and 33 ml of triethylamine and thewhole mixture was further refluxed for 3 hours. After the solvent wasremoved by evaporation, the residue thus obtained was dissolved inchloroform, washed with water then dried with anhydrous magnesiumsulfate. The solvent was removed by evaporation, and the residue thusobtained was recrystallized from ethanol twice, to yield 57.1 g of7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril.

[0238] Colorless flake crystals

[0239] Melting point: 139.0-139.5° C.

[0240] “Method b”: Process for Preparing Conventional Anhydride

[0241] The Method b is described in the Proceedings of the 4thJapanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996).

[0242] Furthermore, the Aripiprazole Anhydride Crystals B of the presentinvention are prepared for example by heating conventional aripiprazolehydrate at 90-125° C. The heating time is generally about 3-50 hours,but cannot be stated unconditionally since it differs depending onheating temperature. The heating time and heating temperature areinversely related, so that for example the heating time will be longerthe lower the heating temperature, and shorter the higher the heatingtemperature. Specifically, if the heating temperature of thearipiprazole hydrate is 100° C., the heating time can be about 24 hours,while if the heating temperature is 120° C., the heating time can beabout 3 hours.

[0243] The aripiprazole hydrate which is the raw material for preparingthe Aripiprazole Anhydride Crystals B of the present invention isprepared for example by Method c below.

[0244] “Method c”: Process for Preparing Conventional Hydrate

[0245] Aripiprazole hydrate is easily obtained by dissolving thearipiprazole anhydride crystals obtained by Method a above in a hydroussolvent, and heating and then cooling the resulting solution. Using thismethod, aripiprazole hydrate is precipitated as crystals in the hydroussolvent.

[0246] An organic solvent containing water is usually used as thehydrous solvent. The organic solvent should be one which is misciblewith water, such as for example an alcohol such as methanol, ethanol,propanol or isopropanol, a ketone such as acetone, an ether such astetrahydrofuran, dimethylformamide, or a mixture thereof, with ethanolbeing particularly desirable. The amount of water in the hydrous solventcan be 10-25% by volume of the solvent, or preferably close to 20% byvolume.

[0247] Medicinal Composition

[0248] A medicinal composition of the present invention will containAripiprazole Anhydride Crystals B, C, D, E, F and G in apharmaceutically acceptable carrier or combination of carriers.

[0249] Carriers which are pharmaceutically acceptable include diluentsand excipients generally used in pharmaceuticals, such as fillers,extenders, binders, moisturizers, disintegrators, surfactants, andlubricants.

[0250] The medicinal composition of the present invention may beformulated as an ordinary medicinal preparation, for example in the formof tablets, flashmelt tablets, pills, powder, liquid, suspension,emulsion, granules, capsules, suppositories or as an injection (liquid,suspension, etc.).

[0251] When a tablet formulation is used, a wide variety of carriersthat are known in the field can be used. Examples include lactose,saccharose, sodium chloride, glucose, xylitol, mannitol, erythritol,sorbitol, urea, starch, calcium carbonate, kaolin, crystal cellulose,silic acid and other excipients; water, ethanol, propanol, simple syrup,glucose liquid, starch liquid, gelatin solution, carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrolidone and other binders; dried starch, sodium alginate, agarpowder, laminaran powder, sodium bicarbonate, calcium carbonate,polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate,monoglyceride stearate, starch, lactose and other disintegrators;saccharose, stearin, cacao butter, hydrogenated oil and otherdisintegration inhibitors; quaternary ammonium salt, sodium laurylsulfate and other absorption promoters; glycerine, starch and othermoisture retainers; starch, lactose, kaolin, bentonite, colloidal silicacid and other adsorbents; and refined talc, stearate, boric acidpowder, polyethylene glycol and other lubricants and the like. Tabletscan also be formulated if necessary as tablets with ordinary coatings,such as sugar-coated tablets, gelatin-coated tablets, enteric coatedtablets and film coated tablets, as well as double tablets andmultilayered tablets.

[0252] When a pill formulation is used, a wide variety of carriers thatare known in the field can be used. Examples include glucose, lactose,starch, cacao butter, hardened vegetable oil, kaolin, talc and otherexcipients; gum arabic powder, traganth powder, gelatin, ethanol andother binders; and laminaran, agar and other disintegrators and thelike.

[0253] When a suppository formulation is used, a wide variety ofcarriers that are known in the field can be used. Examples includepolyethylene glycol, cacao butter, higher alcohol, esters of higheralcohol, gelatin semi-synthetic glyceride and the like.

[0254] Capsules are prepared according to ordinary methods by mixingaripiprazole anhydride crystals with the various carriers describedabove and packing them in hard gelatin capsules, soft capsules,hydroxypropylmethyl cellulose capsules (HPMC capsules) and the like.

[0255] In addition, colorants, preservatives, perfumes, flavorings,sweeteners and the like as well as other drugs may be included in themedicinal composition.

[0256] In case of forming the pharmaceutical solid oral preparation inthe form of granules, it can be prepared by wet granulating a mixedpowder of granulating ingredients comprising, aripiprazole anhydridecrystals (conventional aripiprazole anhydride crystals or aripiprazoleanhydride crystals selected from the group consisting of aripiprazoleanhydride type B, C, D, E, F and G crystals) and various carriers whichare heretofore well-known in this field, such as excipients,disintegrators, disintegration inhibitors, humectants, absorptionaccelerators, adsorbents, lubricants, colorants and the like (for theexamples of these agents, those of previously mentioned can be referredto) by adding a liquid (generally, water or an aqueous solutioncontaining binding agents). As for the wet granulation, there arevarious methods are included, for example, fluidized bed granulation,kneading granulation, extruding granulation, rotating granulation andthe like can be mentioned. Among these methods, in case of conductingthe fluidized bed granulation, the granulating ingredients containingvarious carriers are mixed with inlet air, then upon continuedfluidizing the granulating ingredients and the liquid is sprayed toconduct granulation. In case of conducting the kneading granulation, thegranulating ingredients containing various carriers are mixed byagitation, then upon continued agitating the granulating ingredients,granulation is conducted by adding the liquid. After the granulation, ifnecessary, the obtained granules are sized to make them to the desiredsize by use of a suitable sieve or a mill having suitable screen size.The granules thus obtained by such a method are dried again in additionto usual drying being conducted when preparing the granules. As for thedrying methods, various methods can be applied, for example, methods byuse of a fluidized bed dryer, a fan dryer, a vacuum dryer and the likecan be mentioned. Generally, drying methods can be conducted underconventional conditions, for example, in case of using the fluidized beddryer, drying procedure is conducted with an air flow of 0.5 m³/min to50 m³/min, an inlet air temperature at 70 to 100° C. for 10 min to 1hour. After dried, the granules are subjected to size, then furtherdried. In case of using the fluidized bed dryer or fan dryer or thelike, the drying procedure is conducted under the conditions with an airflow of 0.5 m³/min to 50 m³/min, an inlet air temperature at 70 to 100°C. for 1 to 6 hours. In case of using the vacuum dryer, the dryingprocedure is conducted under the conditions of reduced pressure of aboutat 0-10 torr of degree of vacuum at 70 to 100° C. of jacket temperaturefor 1 to 6 hour.

[0257] The thus prepared granules may be used as they are for thepharmaceucal solid oral preparations, or if necessary, they may beshaped in the form of tablets. Further, the dried granules dried byusual manner are shaped in the form of tablets, then they may be driedagain.

[0258] The thus prepared pharmaceutical solid oral preparationcomprising aripiprazole anhydride crystals hardly changes to hydrateseven if they are stored for a long period of time, therefore thepharmaceutical solid oral preparation, of which dissolution rate doesnot hardly lowered (dissolution rate to maintain maximum drugconcentration (Cmax): 60% or higher dissolution rate obtained after 30minutes at pH 4.5, 70% or higher dissolution rate obtained after 60minutes at pH 4.5, or 55% or higher dissolution rate obtained after 60minutes at pH 5.0) can be provided.

[0259] Another pharamceutical solid oral preparation can be provided bygranulating a conventional aripiprazole hydrate crystals by a methodsimilar to that of mentioned above, and dried by usual manner undersimilar conditions, then dried again. Alternatively, the dried granulesdried by usual manner are shaped to tablets form, then they are driedagain, then pharmaceutical solid oral preparations of which dissolutionrate does not lowered (dissolution rate to maintain maximum drugconcentration (Cmax): 60% or higher dissolution rate obtained after 30minutes at pH 4.5, 70% or higher dissolution rate obtained after 60minutes at pH 4.5 or 55% or higher dissolution rate obtained after 60minutes at pH 5.0) can be provided. These facts can be understood that,the conventional aripiprazole anhydride crystals or the aripiprazolehydrate crystals contained in the pharmaceutical solid oral preparationare changed to “B type crystals” of aripiprazole anhydride by dryingtwice.

[0260] The amount of Aripiprazole Anhydride Crystals B, C, D, E, F and Gthat should be included in the medicinal composition of the presentinvention can be selected from a wide range suitable for the indicationsought to be treated. Generally, the Aripiprazole Anhydride Crystals Bshould be present in about 1-70% by weight or particularly about 1-30%by weight based on the medicinal composition.

[0261] The method of administration of the medicinal composition of thepresent invention may be adjusted to suit, for example, the formulationof the drug product, the age, gender and other conditions (including theseverity thereof) of the patient. In the case of tablets, pills,liquids, suspensions, emulsions, granules and capsules, for example,administration is oral. In the case of an injection, it is administeredintravenously either by itself or mixed with an ordinary replenishersuch as glucose or amino acids, or may also be administered by itselfintramuscularly, intracutaneously, subcutaneously or intraperitoneally,as necessary. In the case of a suppository, administration isintrarectal.

[0262] The dosage of the medicinal composition of the present inventionis selected depending on the usage, the age, gender and other conditionsof the patient, the severity of the condition and so forth, butordinarily the amount of aripiprazole anhydride crystals can be about0.1-10 mg per 1 kg of body weight per day. The preparation which is theunit of administration should contain in the range of about 1-100 mg ofAripiprazole Anhydride Crystals B, more particularly 1-30 mg per unitdose.

[0263] The medicinal composition of the present invention is extremelystable, with substantially no decrease in solubility even when storedfor long periods of time.

[0264] The medicinal composition of the present invention is effectivein the prevention and treatment of central nervous system disorders suchas schizophrenia and may also be effective in the treatment ofintractable (drug-resistant, chronic) schizophrenia with cognitiveimpairment and intractable (drug-resistant, chronic) schizophreniawithout cognitive impairment, anxiety including mild anxiety, maniaincluding bipolar disorder acute mania and acute mania, bipolardisorder, depression including bipolar disorder depression, autism,Down's syndrome, attention deficit hyperactivity disorder (ADHD),Alzheimer's disease, Parkinson's disease and other neurodegenerativediseases, panic, obsessive compulsive disorder (OCD), sleep disorders,sexual dysfunction, alcohol and drug dependency, vomiting, motionsickness, obesity, miparticlee headache and cognitive impairment.

[0265] Analytical Methods

[0266] (1) The ¹H-NMR spectrum was measured in DMSO-d₆ using TMS as thestandard.

[0267] (2) Powder X-ray Diffraction

[0268] Using a Rigaku Denki RAD-2B diffraction meter, the powder x-raydiffraction pattern was measured at room temperature using a Cu Kafilled tube (35 kV 20 mA) as the x-ray source with a wide-anglegoniometer, a 1° scattering slit, an 0.15 mm light-intercepting slit, agraphite secondary monochromator and a scintillation counter. Datacollection was done in 2θ continuous scan mode at a scan speed of5°/minute in scan steps of 0.02° in the range of 3° to 40°.

[0269] (3) The IR spectrum was measured by the KBr method.

[0270] (4) Thermogravimetric/Differential Thermal Analysis

[0271] Thermogravimetric/differential thermal analysis was performedusing a Seiko SSC 5200 control unit and a TG/DTA 220 simultaneousdifferential thermal/thermogravimetric measurement unit. 5-10 mg sampleswere placed in open aluminum pans and heated from 20° C. to 200° C. in adry nitrogen atmosphere at a heating rate of 5° C./minute. α-alumina wasused as the standard substance.

[0272] (5) Differential Scanning Calorimetry

[0273] Thermogravimetric/differential thermal analysis was performedusing a Seiko SSC 5200 control unit and a DSC 220C differential scanningcalorimeter. 5-10 mg samples were placed in crimped aluminum pans andheated from 20° C. to 200° C. in a dry nitrogen atmosphere at a heatingrate of 5° C./minute. α-alumina was used as the standard substance.

[0274] (6) Particle Size Measurement

[0275] 0.1 g of the particles to be measured were suspended in a 20 mln-hexane solution of 0.5 g soy lecithin, and particle size was measuredusing a size distribution meter (Microtrack HRA, Microtrack Co.).

[0276] (7) Hygroscopicity Test Method

[0277] One g of the sample was accurately weighed in a weighing bottle(diameter 5 cm), covered with kimwipes and left to rest in a 60° C./100%RH environment (water/dessicator). 24 hours later, the weighing bottlewas removed, transferred to an environment of a room temperature andabout 30% RH (magnesium chloride hexahydrate saturated watersolution/dessicator) and left to rest for 24 hours and the water contentof the sample was measured by the Karl Fischer method.

[0278] (8) Solid ¹³C-NMR Spectrometry

[0279] Solid ¹³C-NMR spectrum was measured under the conditions asfollows.

[0280] Measuring apparatus: CMX-360 Solid State NMR Spectrometer(manufactured by Chemagnetic Inc.)

[0281] Computer: SPARC Station 2 (manufactured by SUN Microsystem, Inc.)

[0282] OS, Software: Solalis 1.1.1 Rev. B (Registered trademark: UNIX),Spinsight Ver. 2.5

[0283] Name of measured pulse: TOSS method (TOSS is a program name ofthe apparatus) among CP/MAS method.

[0284] Width of measured puls: 90° puls was used under the condition ofCP.

[0285] Measuring sample tube: Test tube made of zirconia, having theoutside diameter of 7.5 mm, and inside capacity of 0.8 ml

[0286] Revolution: 4250 Hz (Revolution per second Contact time: 1 msec.

[0287] Waiting time: 20 sec.

[0288] Integrated times: 512 times

[0289] Measuring temperature: About 25° C. temperature of outside oftest tube)

[0290] External standard: Methyl group (δ 17.3) of hexamethylbenzene wasused as the external standard.

[0291] The present invention is explained in more detail below usingreference examples, examples, sample preparations and formulationexamples.

REFERENCE EXAMPLE 1

[0292] 19.4 g of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril and 16.2 g of1-(2,3-dichlorophenyl) piperadine 1 hydrochloride were added to 8.39 gof potassium carbonate dissolved in 140 ml of water, and circulated for3 hours under agitation. After reaction the mixture was cooled and theprecipitated crystals filtered out. These crystals were dissolved in 350ml of ethyl acetate, and about 210 ml of water/ethyl acetate azeotroperemoved under reflux. The remaining solution was cooled, and theprecipitated crystals filtered out. The resulting crystals were driedfor 14 hours at 60° C. to produce 20.4 g (74.2%) of raw aripiprazole.

[0293] 30 g of the raw aripiprazole obtained above was recrystallizedfrom 450 ml of ethanol according to the methods described in JapaneseUnexamined Patent Publication No. 191256/1990, and the resultingcrystals dried for 40 hours at 80° C. to obtain aripiprazole anhydridecrystals. The yield was 29.4 g (98.0%).

[0294] The melting point (mp) of these aripiprazole anhydride crystalswas 140° C., matching the melting point of the aripiprazole anhydridecrystals described in Japanese Unexamined Patent Publication No.191256/1990.

[0295] When these crystals were left for 24 hours in a dessicator set athumidity 100%, temperature 60° C., they exhibited hygroscopicity of3.28% (see Table 1 below).

REFERENCE EXAMPLE 2

[0296] 6930 g of the intermediate raw aripiprazole obtained in ReferenceExample 1 was heat dissolved in 138 liters of hydrous ethanol (watercontent 20%) according to the method presented at the 4thJapanese-Korean Symposium on Separation Technology, gradually (2-3hours) cooled to room temperature, and then chilled to near 0° C. Theprecipitated crystals were filtered out, producing about 7200 g ofaripiprazole hydrate (wet state).

[0297] The wet-state aripiprazole hydrate crystals obtained above weredried for 30 hours at 80° C. to obtain 6480 g (93.5%) of conventionalaripiprazole anhydride crystals. The melting point (mp) of thesecrystals was 139.5° C. These crystals were confirmed by the Karl Fischermethod to be anhydrous, with a moisture value of 0.03%.

[0298] When left for 24 hours in a dessicator set at humidity 100%,temperature 60° C., these crystals exhibited hygroscopicity of 1.78%(see Table 1 below).

REFERENCE EXAMPLE 3

[0299] 820 g of the intermediate wet-state aripiprazole hydrate obtainedin Reference Example 2 was dried for 2 hours at 50° C. to obtain 780 gof aripiprazole hydrate crystals. These crystals had a moisture value of3.82% according to the Karl Fischer method. As shown in FIG. 6,thermogravimetric/differential thermal analysis revealed endothermicpeaks at 75.0, 123.5 and 140.5° C. Because dehydration began near 70°C., there was no clear melting point (mp).

[0300] As shown in FIG. 7, the powder x-ray diffraction spectrum ofaripiprazole hydrate obtained by this method exhibited characteristicpeaks at 2θ=12.6°, 15.1°, 17.4°, 18.2°, 18.7°, 24.8° and 27.5°.

[0301] The powder x-ray diffraction spectrum of this aripiprazolehydrate was identical to the powder x-ray diffraction spectrum ofaripiprazole hydrate presented at the 4th Joint Japanese-KoreanSymposium on Isolation Technology.

REFERENCE EXAMPLE 4

[0302] Preparation of 15 mg tablets containing type I crystals ofaripiprazole anhydride obtained in Reference Example 2.

[0303] Type-I crystals of aripiprazole anhydride (525 g), lactose (1,995g), corn starch (350 g) and crystalline cellulose (350 g) were chargedin a fluidized bed granulating dryer (Flow coater FLO-5, manufactured byFREUND INDUSTRIAL CO., LTD.), and these granulating ingredients weremixed by fluidizing for about 3 minutes with an inlet air temperature at70° C. and air flow rate of 3 m³/min. Further, the granulatingingredients were upon continued fluidizing under the same condition andsprayed about 1,400 g of the aqueous solution to obtained wet granules.The wet granules were dried under inlet air at temperature at 80° C.,for about 15 minutes. The obtained dried granules contained 4.3% ofwater. (Yield: 99%). The dried granules were subjected to sizing bypassing to a sieve of 710 μm.

[0304] About 1% by weight of magnesium stearate was added to the sizedgranules and mixed, then the granules were supplied to a tablet machine(Rotary single tablet press 12HUK: manufactured by KIKUSUI SEISAKUSHOCO., LTD.), there were obtained tablets, each having 95 mg of weight.

[0305] Water content of the tablets was measured according to volumetrictitration method (Karl-Fischer method) described in water contentmeasuring method in Japanese Pharmacopoea or the electrical quantitytitration method.

[0306] Water content measuring method:

[0307] Sample (0.1 to 0.5 g) (in case of a tablet, 1 tablet was used)was weighed precisely, and the water content was measured by use of awater content measuring equipment.

[0308] Volumetric titration:

[0309] Automated water content measuring equipment Model: KF-06(manufacture by MITSUBISHI CHEMICAL CORP.)

[0310] Electrical quantity titration method:

[0311] Automated micro-water content measuring equipment Model: AQ-7F(manufactured by HIRANUMA SANGYO CO., LTD.)

[0312] Automated water vaporization equipment Model:

[0313] LE-20S (manufactured by HIRANUMA SANGYO CO., LTD.)

[0314] Heating temperature: 165±10° C.

[0315] Nitrogen gas flow rate: about 150 ml/min.

REFERENCE EXAMPLE 5

[0316] Preparation of 15 mg tablets containing type B crystals ofaripiprazole anhydride

[0317] Type B crystals of aripipraole anhydride (4,500 g), lactose(17,100 g), corn starch (3,000 g) and crystalline cellulose (3,000 g)were charged in a fluidized bed granulating dryer (NEW-MARUMERIZERModel: NQ-500, manufactured by FUJI PAUDAL CO., LTD.), and thesegranulating ingredients were mixed by fluidizing for about 3 minuteswith an inlet air temperature at 70° C., air flow rate of 10 to 15m³/min. Further, the granulating ingredients were upon continuedfluidizing under the same condition, and sprayed about 12,000 g of 5%aqueous solution of hydroxypropyl celulose to obtained wet granules. Thewet granules were dried under inlet air at temperature at 85° C., forabout 28 minutes. The thus obtained dried granules contained 3.8% ofwater (measured by the method according to Reference Example 4). (Yield:96%). The dried granules were subjected to sizing by passing to a sieveof 850 μm.

[0318] About 1% by weight of magnesium stearate was added to the sizedgranules and mixed, then the granules were supplied to a tablet machine(Rotary single tablet press 12HUK: manufactured by KIKUSUI SEISAKUSHOCO., LTD.), there were obtained tablets, each having 95 mg of weight.

Example 1

[0319] 500.3 g of the aripiprazole hydrate crystals obtained inReference Example 3 were milled using a sample mill (small atomizer).The main axis rotation rate was set to 12,000 rpm and the feed rotationrate to 17 rpm, and a 1.0 mm herringbone screen was used. Milling wascompleted in 3 minutes, resulting in 474.6 g (94.9%) of AripiprazoleHydrate A powder.

[0320] The Aripiprazole Hydrate A (powder) obtained in this way had amean particle size of 20-25 μm. The melting point (mp) was undeterminedbecause dehydration was observed beginning near 70° C.

[0321] The Aripiprazole Hydrate A (powder) obtained above exhibited an¹H-NMR (DMSO-d₆, TMS) spectrum which was substantially the same as the¹H-NMR spectrum shown in FIG. 2. Specifically, it had characteristicpeaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m,4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm(brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz,1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

[0322] The Aripiprazole Hydrate A (powder) obtained above had a powderx-ray diffraction spectrum which was substantially the same as thepowder x-ray diffraction spectrum shown in FIG. 3. Specifically, it hadcharacteristic peaks 2θ=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5° and24.8°. This pattern is different from the powder x-ray spectrum ofunmilled aripiprazole hydrate shown in FIG. 7.

[0323] The Aripiprazole Hydrate A (powder) obtained above had infraredabsorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and784 cm⁻¹ on the IR (KBr) spectrum.

[0324] As shown in FIG. 1, the Aripiprazole Hydrate A (powder) obtainedabove had a weak peak at 71.3° C. in thermogravimetric/differentialthermal analysis and a broad endothermic peak (weight loss observedcorresponding to one water molecule) between 60-120° C.—clearlydifferent from the endothermic curve of unmilled aripiprazole hydrate(see FIG. 6).

Example 2

[0325] 450 g of the Aripiprazole Hydrate A (powder) obtained in Example1 was dried for 24 hours at 100° C. using a hot air dryer to produce 427g (yield 98.7%) of Aripiprazole Anhydride Crystals B.

[0326] These Aripiprazole Anhydride Crystals B had a melting point (mp)of 139.7° C.

[0327] The Aripiprazole Anhydride Crystals B obtained above had an¹H-NMR spectrum (DMSO-d₆, TMS) which was substantially the same as the¹H-NMR spectrum shown in FIG. 4. Specifically, they had characteristicpeaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m,4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm(brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz,1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

[0328] The Aripiprazole Anhydride Crystals B obtained above had a powderx-ray diffraction spectrum which was substantially the same as thepowder x-ray diffraction spectrum shown in FIG. 5. Specifically, theyhad characteristic peaks 2θ=11.0°, 16.6°, 19.3°, 20.3° and 22.1°.

[0329] The Aripiprazole Anhydride Crystals B obtained above hadremarkable infrared absorption bands at 2945, 2812, 1678, 1627, 1448,1377, 1173, 960 and 779 cm⁻¹ on the IR (KBr) spectrum.

[0330] The Aripiprazole Anhydride Crystals B obtained above exhibited anendothermic peak near about 141.5° C. in thermogravimetric/differentialthermal analysis.

[0331] The Aripiprazole Anhydride Crystals B obtained above exhibited anendothermic peak near about 140.7° C. in differential scanningcalorimetry.

[0332] Even when the Aripiprazole Anhydride Crystals B obtained abovewere left for 24 hours in a dessicator set at humidity 100%, temperature60° C., they did not exhibit hygroscopicity exceeding 0.4% (See Table 1below).

Example 3

[0333] 44.29 kg of the Aripiprazole Hydrate A (powder) obtained inExample 1 was dry heated for 18 hours in a 100° C. hot air dryer andthen heated for 3 hours at 120° C. to produce 42.46 kg (yield 99.3%) ofAripiprazole Anhydride Crystals B.

[0334] The physicochemical properties of the resulting AripiprazoleAnhydride Crystals B were the same as the physicochemical properties ofthe Aripiprazole Anhydride Crystals B obtained in Example 2.

[0335] The Aripiprazole Anhydride Crystals B obtained in this way didnot exhibit hygroscopicity of more than 0.4% even when left for 24 hoursin a dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 4

[0336] 40.67 kg of the Aripiprazole Hydrate A (powder) obtained inExample 1 was dry heated for 18 hours in a 100° C. hot air dryer andthen heated for 3 hours at 120° C. to produce 38.95 kg (yield 99.6%) ofAripiprazole Anhydride Crystals B.

[0337] The physicochemical properties of the resulting AripiprazoleAnhydride Crystals B were the same as the physicochemical properties ofthe Aripiprazole Anhydride Crystals B obtained in Example 2.

[0338] The Aripiprazole Anhydride Crystals B obtained in this way didnot exhibit hygroscopicity of more than 0.4% even when left for 24 hoursin a dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

[0339] Examples 5-10 are useful for injectable or oral solutionformulations but not solid dose formulations since they were made byheating Conventional Anhydride or Conventional Hydrate instead ofHydrate A.

Example 5

[0340] The hygroscopic aripiprazole anhydride crystals obtained inReference Example 1 were heated for 50 hours at 100° C. using the samemethods as in Example 2. The physicochemical properties of the resultingAripiprazole Anhydride Crystals B were the same as the physicochemicalproperties of the Aripiprazole Anhydride Crystals B obtained in Example2.

[0341] The Aripiprazole Anhydride Crystals B obtained in this way didnot exhibit hygroscopicity of more than 0.4% even when left for 24 hoursin a dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 6

[0342] The hygroscopic aripiprazole anhydride crystals obtained inReference Example 1 were heated for 3 hours at 120° C. using the samemethods as in Example 2. The physicochemical properties of the resultingAripiprazole Anhydride Crystals B were the same as the physicochemicalproperties of the Aripiprazole Anhydride Crystals B obtained in Example2.

[0343] The Aripiprazole Anhydride Crystals B obtained in this way didnot exhibit hygroscopicity of more than 0.4% even when left for 24 hoursin a dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 7

[0344] The hygroscopic aripiprazole anhydride crystals obtained inReference Example 2 were heated for 50 hours at 100° C. using the samemethods as in Example 2. The physicochemical properties of the resultingAripiprazole Anhydride Crystals B were the same as the physicochemicalproperties of the Aripiprazole Anhydride Crystals B obtained in Example2.

[0345] The Aripiprazole Anhydride Crystals B obtained in this way didnot exhibit hygroscopicity of more than 0.4% even when left for 24 hoursin a dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 8

[0346] The hygroscopic aripiprazole anhydride crystals obtained inReference Example 2 were heated for 3 hours at 120° C. using the samemethods as in Example 2. The physicochemical properties of the resultingAripiprazole Anhydride Crystals B were the same as the physicochemicalproperties of the Aripiprazole Anhydride Crystals B obtained in Example2.

[0347] The Aripiprazole Anhydride Crystals B obtained in this way didnot exhibit hygroscopicity of more than 0.4% even when left for 24 hoursin a dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 9

[0348] The aripiprazole hydrate crystals obtained in Reference Example 3were heated for 50 hours at 100° C. using the same methods as in Example2. The physicochemical properties of the resulting AripiprazoleAnhydride Crystals B were the same as the physicochemical properties ofthe Aripiprazole Anhydride Crystals B obtained in Example 2.

[0349] The Aripiprazole Anhydride Crystals B obtained in this way didnot exhibit hygroscopicity of more than 0.4% even when left for 24 hoursin a dessicator set at humidity 100%, temperature 60° C. (see Table 1below).

Example 10

[0350] The aripiprazole hydrate crystals obtained in Reference Example 3were heated for 3 hours at 120° C. using the same methods as in Example2. The physicochemical properties of the resulting AripiprazoleAnhydride Crystals B were the same as the physicochemical properties ofthe Aripiprazole Anhydride Crystals B obtained in Example 2.

[0351] The Aripiprazole Anhydride Crystals B obtained in this wayexhibited hygroscopicity of no more than 0.4% even when left for 24hours in a dessicator set at humidity 100%, temperature 60° C. (seeTable 1 below).

Example 11

[0352] (Preparation of Type C Crystals of Aripiprazole Anhydride)

[0353] 100 Miligrams of type-I crystals of aripiprazole anhydrideobtained in Reference Example 2 were heated about 145° C. (±3° C.). Inthis occasion, there was observed the phenomena that the crystals wereonce melted, then again crystallized. After that, 100 mg (yield: 100%)of Type C crystals of aripiprazole anhydride were obtained. The meltingpoint of the crystals was 150° C. The crystals were colorless prismform.

[0354] The type C crystals of aripiprazole anhydride obtained above hadan endothermic curve which was substantially identical to theendothermic curve of hermogravimetric/differential thermal analysis(heating rate: 5° C./minute) shown in FIG. 8. Specifically, it showedthe endothermic curve around 150.2° C.

[0355] The type C crystals of aripiprazole anhydride thus obtainedexhibited an ¹H-NMR spectrum (DMSO-d₆, TMS) which was substantiallyidentical to the ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 9.Specifically, it had the characteristic peaks at 1.55-1.63 ppm (m, 2H),1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),7.28-7.32 ppm (m, 2H), and 10.00 ppm (s, 1H).

[0356] The type C crystals of aripiprazole anhydride obtained above hada powder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 10. Specifically, ithad the characteristic peaks 2θ=12.6°, 13.7°, 15.4°, 18.1°, 19.0°,20.6°, 23.5° and 26.4°.

[0357] The type C crystals of aripiprazole anhydride obtained above hadan IR spectrum which was substantially identical to the IR (KBr)spectrum shown in FIG. 11. Specifically, it had the characteristicinfrared absorption bands at 2939, 2804, 1680, 1375 and 780 cm⁻¹.

[0358] The type C crystals of aripiprazole anhydride obtained aboveexhibited a solid ¹³C-NMR spectrum, which was substantially identical tothe solid ¹³C-NMR spectrum shown in FIG. 12. Specifically, it had thecharacteristic peaks at 32.8 ppm, 60.8 ppm, 74.9 ppm, 104.9 ppm, 152.2ppm, 159.9 ppm and 175.2 ppm.

[0359] According to the above-mentioned data on endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of thetype C crystals of aripiprazole anhydride was confirmed.

[0360] When the type C crystals of aripiprazole anhydride crystalsobtained above were left for 24 hours in a dessicator where theconditions were set at humidity 100%, and temperature 60° C., then thecrystals did not exhibit hygroscopicity higher than 0.4% (see, Table 1below).

Example 12

[0361] (Preparation of Type D Crystals of Aripiprazole Anhydride)

[0362] The type-I crystals of aripiprazole anhydride obtained inReference Example 2 were added in 200 ml of toluene, and dissolved byheating at 74° C. After confirmed that it was dissolved completely, thetoluene solution was cooled to 7° C., and the precipitated crystals werecollected by filtration. The crystals were subjected to air-drying asthey were so as to obtain 17.9 g (yield: 89.5%) of type D crystals ofaripiprazole anhydride.

[0363] The type D crystals of aripiprazole anhydride obtained above hadan endothermic curve substantially identical to the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) shown in FIG. 13. Specifically, it had the endothermic peaksat about 136.8° C. and about 141.6°.

[0364] The type D crystals of aripiprazole anhydride obtained aboveexhibited ¹H-NMR spectrum (DMSO-d₆, TMS) which was substantiallyidentical to the ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 14.Specifically, they had the characteristic peaks at 1.55-1.63 ppm (m,2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),7.28-7.32 ppm (m, 2H), and 10.00 ppm (s, 1H).

[0365] The type D crystals of aripiprazole anhydride obtained above hada powder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 15. Specifically, ithad the characteristic peaks 2θ=8.7°, 11.6°, 16.3°, 17.7°, 18.6°, 20.3°,23.4° and 25.0°.

[0366] The type D crystals of aripiprazole anhydride obtained above hadan IR spectrum which was substantially identical to the IR (KBr)spectrum shown in FIG. 16. Specifically, it had the characteristicinfrared absorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm⁻¹.

[0367] The type D crystals of aripiprazole anhydride obtained aboveexhibited a solid ¹³C-NMR spectrum which was substantially identical tothe solid ¹³C-NMR spectrum shown in FIG. 17. Specifically, it had thecharacteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4ppm, 158.5 ppm and 174.1 ppm.

[0368] According to the above-mentioned data on the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of typeD crystals of aripiprazole anhydride was confirmed.

[0369] When the type D crystals of aripiprazole anhydride crystalsobtained above were left for 24 hours in a dessicator where theconditions were set at humidity 100%, and temperature 60° C., thecrystals did not have hygroscopicity higher than 0.4% (see, Table 1below).

Example 13

[0370] (Preparation of Type D Crystals of Aripiprazole Anhydride)

[0371] 1,200 Grams of the type-I crystals of aripiprazole anhydrideobtained in Reference Example 2 were dissolved in 18 liters of toluene,with heating. This toluene solution was cooled to 40° C., and 36 g oftype-D crystals of aripiprazole anhydride obtained in Example 12 wereadded as seed crystals, then the solution was cooled to 10° C. andallowed to stand as it is. The precipitated crystals were collected byfiltration, dried at 60° C. for 18 hours to obtain 1,073 g (yield:86.8%) of type D crystals of aripiprazole anhyride (purity: 100%). Thecrystals were colorless plate form.

[0372] The type D crystals of aripiprazole anhydride had an endothermiccurve substantially identical to the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) shown in FIG. 13. Specifically, it had the endothermic peaksaround about 136.8° C. and about 141.6°.

[0373] The type D crystals of aripiprazole anhydride obtained aboveexhibited an ¹H-NMR spectrum (DMSO-d₆, TMS) which was substantiallyidentical to the ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 14.Specifically, it had the characteristic peaks at 1.55-1.63 ppm (m, 2H),1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),7.28-7.32 ppm (m, 2H), and 10.00 ppm (s, 1H).

[0374] The type D crystals of aripiprazole anhydride obtained above hada powder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 15. Specifically, ithad the characteristic peaks 2θ=8.7°, 11.6°, 16.3°, 17.7°, 18.6°, 20.3°,23.4° and 25.0°.

[0375] The type D crystals of aripiprazole anhydride obtained above hadan IR spectrum which was substantially identical to the IR (KBr)spectrum shown in FIG. 16. Specifically, it had characteristic infraredabsorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm⁻¹.

[0376] The type D crystals of aripiprazole anhydride obtained above hada solid ¹³C-NMR spectrum which was substantially identical to the solid¹³C-NMR spectrum shown in FIG. 17. Specifically, it had thecharacteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4ppm, 158.5 ppm and 174.1 ppm.

[0377] According to the above-mentioned data on the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of typeD crystals of aripiprazole anhydride was confirmed.

[0378] When the type D crystals of aripiprazole anhydride crystalsobtained above were left for 24 hours in a dessicator where theconditions were set at humidity 100%, and temperature 60° C., thecrystals did not exhibit hygroscopicity higher than 0.4% (see, Table 1below).

Example 14

[0379] (Preparation of Type E Crystals of Aripiprazole Anhydride)

[0380] 40 Grams of type-I crystals of aripiprazole anhydride obtained inReference Example 2 was dissolved in 1000 ml of acetonitrile withheating at 80° C. This acetonitrile solution was cooled to about 70° C.by taking for about 10 minutes, and was kept at this temperature forabout 30 minutes to precipitate the seed crystals. Next, the temperatureof said solution was slowly risen to 75° C., and the crystals were grownup by keeping this temperature for 1 hour. Then, the solution was cooledto 10° C. by taking about 4 hours, and the precipitated crystals werecollected by filtration. Thus obtained crystals were subjected toair-drying overnight, there were obtained 37.28 g (yield: 93.2%) of typeE crystals of aripiprazole anhydride (purity: 100%). The melting pointof these crystals was 145° C., and the crystals were colorless needleform.

[0381] The type E crystals of aripiprazole anhydride had an endothermiccurve substantially identical to the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) shown in FIG. 18. Specifically, it had endothermic peak atabout 146.5°.

[0382] The type E crystals of aripiprazole anhydride obtained aboveexhibited an ¹H-NMR spectrum (DMSO-d₆, TMS) which was substantiallyidentical to the ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 19.Specifically, it had the characteristic peaks at 1.55-1.63 ppm (m, 2H),1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),7.28-7.32 ppm (m, 2H), and 10.00 ppm (s, 1H).

[0383] The type E crystals of aripiprazole anhydride obtained above hada powder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 20. Specifically, ithad the characteristic peaks 2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5° and24.0°.

[0384] The type E crystals of aripiprazole anhydride obtained above hadan IR spectrum which was substantially identical to the IR (KBr)spectrum shown in FIG. 21. Specifically, it had the characteristicinfrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969 and 774cm⁻¹.

[0385] According to the data on the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of typeE crystals of aripiprazole anhydride was confirmed.

[0386] When the type E crystals of aripiprazole anhydride obtained abovewere left for 24 hours in a dessicator where the conditions were set athumidity 100%, and temperature 60° C., the crystals did not exhibithygroscopicity higher than 0.4% (see, Table 1 below).

Example 15

[0387] (Preparation of Type F Crystals of Aripiprazole Anhydride)

[0388] 140 Grams of type-I crystals of aripiprazole anhydride obtainedin Reference Example 2 were suspended in 980 ml of acetone and continuedto reflux for 7.5 hours with stirring. Next, the suspension was filteredin hot condition, and crystals separated out were subjected toair-drying for 16 hours at room temperature, there was obtained 86.19 g(yield: 61.6%) of type F crystals of aripiprazole anhydride (purity:100%). The crystals were colorless prism form.

[0389] The type F crystals of aripiprazole anhydride had an endothermiccurve substantially identical to the endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) shown in FIG. 22. Specifically, it had the exothermic peaksat about 137.5° C. and about 149.8° C.

[0390] The type F crystals of aripiprazole anhydride obtained aboveexhibited an ¹H-NMR spectrum (DMSO-d₆, TMS) which was substantiallyidentical to the ¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 23.Specifically, it had the characteristic peaks at 1.55-1.63 ppm (m, 2H),1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),7.28-7.32 ppm (m, 2H), and 10.00 ppm (s, 1H).

[0391] The type F crystals of aripiprazole anhydride obtained above hada powder X-ray diffraction spectrum which was substantially identical tothe powder X-ray diffraction spectrum shown in FIG. 24. Specifically, ithad the characteristic peaks 2θ=11.3°, 13.3°, 15.4°, 22.8°, 25.2° and26.9°.

[0392] The type F crystals of aripiprazole anhydride obtained above hadan IR spectrum which was substantially identical to the IR (KBr)spectrum shown in FIG. 25. Specifically, it had the characteristicinfrared absorption bands at 2940, 2815, 1679, 1383, 1273, 1177, 1035,963 and 790 cm⁻¹

[0393] According to the data on endothermic curve ofthermogravimetric/differential thermal analysis (heating rate: 5°C./minute) and powder X-ray diffraction spectrum, the formation of typeF crystals of aripiprazole anhydride was confirmed.

[0394] When the type F crystals of aripiprazole anhydride crystalsobtained above were left for 24 hours in a dessicator where theconditions were set at humidity 100%, and temperature 60° C., thecrystals did not exhibit hygroscopicity higher than 0.4% (see, Table 1below). TABLE 1 Initial Moisture Moisture Content Sample Content (%)After 24 hrs (%) Reference Example 1 0.04 3.28 Reference Example 2 0.041.78 Example 2 0.04 0.04 Example 3 0.02 0.02 Example 4 0.02 0.02 Example5 0.04 0.04 Example 6 0.04 0.04 Example 7 0.04 0.03 Example 8 0.04 0.03Example 9 0.03 0.01 Example 10 0.05 0.05 Example 11 0.03 0.03 Example 120.04 0.03 Example 13 0.04 0.03 Example 14 0.06 0.09 Example 15 0.04 0.04

Example 16

[0395] a) Type I crystals of aripiprazole anhydride (10 g) obtained inReference Example 2 was charged in a stainless steel round tray(diameter: 80 mm), and heated to about 170° C. so as to meltedcompletely. When this melted liquid was cooled, then it solidifiedclarity with pale brawn in color, the solid was peeled off from thestainless steel round tray, there was obtained 9.8 g (yield: 98%) ofglassy state of aripiprazole anhydride. The obtained glassy stateproduct was characterized by having no significant peak observed in apowder X-ray determination. (cf. FIG. 31).

[0396] According to the thermogravimetric/differental thermal analysis(heating rate: 5° C./minute), as shown in FIG. 30, an exothermic peak oftype B crystals of aripiprazole anhydride was observed at around 86.5°C. While, an endothermic peak of type B crystals of aripiprazoleanhydride owing to melting was observed at around 140.1° C.

[0397] b) When the glassy state of aripiprazole anhydride obtained inExample 16-a) were charged in a sealed vessel and left to stand at roomtemperature for about 6 months, then type G crystals of aripiprazoleanhydride having white in color was obtained by changing the color frompale brown (25 g, yield: 100%). Melting point: 138 to 139° C.

[0398] The type G crystals of aripiprazole anhydride had an endothermiccurve which was substantially identical to thethermogravimetric/differential thermal analysis (heating rate: 5°C./min.) endothermic curve shown in FIG. 26, more particulaly, it has anendothermic peak around 141.0° C. and an exothermic peak around 122.7°C.

[0399] The type G crystals of aripiprazole anhydride obtained as aboveexhibited an ¹H-NMR spectrum which was substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 27. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

[0400] The type G crystals of aripiprazole anhydride obtained as abovehad a powder X-ray diffraction spectrum which was substantiallyidentical to the powder X-ray diffraction spectrum shown in FIG. 28.Specifically, it has characteristic peak 2θ=10.1°, 12.8°, 15.2°, 17.0°,17.5°, 19.1°, 20.1°, 21.2°, 22.4°, 23.3°, 24.5° and 25.8°.

[0401] The type G crystals of aripiprazole anhydride obtained above hadan IR spectrum which was substantially identical to the IR (KBr)spectrum shown in FIG. 29. Specifically, it has clear infraredabsorption bands at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787cm⁻¹.

Example 17

[0402] a) Preparation of granules of 30 mg tablets containing type Bcrystals of aripiprazole anhydride for additional drying

[0403] Type B crystals of aripiprazole anhydride (1,500 g), lactose(5,700 g), corn starch (1,000 g) and crystalline cellulose (1,000 g)were charged in a fluidized bed granulating dryer (Flow Coater ModelFLO-5M; manufactured by FROINT SANGYO KABUSHIKI KAISHA), and thesegranulating ingredients were mixed by fluidizing for about 3 minuteswith an inlet air temperature at 60° C., air flow rate of 3 to 4 m³/min.Further, the granulating ingredients were continued fluidizing under thesame condition, and sprayed with about 4,000 g of 5% aqueous solution ofhydroxypropyl celulose to obtain wet granules. The wet granules weredried under an inlet air temperature at 85° C., for about 20 minutes.The obtained dried granules contained 3.8% of water (measured by themethod according to Reference Example 4).

[0404] b) The dried granules (4 kg) obtained in Example 17-a) were sizedby use of a mill (FIORE F-0: manufactured by TOKUJU CORPORATION).

[0405] The sized granules (3 kg) were charged in a fluidized bedgranulating dryer (Flow Coater Model FLO-5M; manufactured by FREUNDINDUSTRIAL CO., LTD.), and these granulating ingredients were driedunder an inlet air temperature at 85° C., and air flow rate of 2 m³/minfor 2 hours. The obtained dried granules contained 3.6% of water(measured by the method according to Reference Example 4).

[0406] About 1% by weight of of magnesium stearate was added to thesized granules and mixed, then the granules were supplied to atabletting machine (a Rotary single tablet press, Model VIRGO:manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and there were obtainedtablets, each having 190 mg of weight.

[0407] c) The dried granules (3 kg) obtained in Example 17-a) werecharged in a vacuum dryer (vacuum granulating dryer model; VG-50:manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and dried at 70° C. of ajacket temperature, under a reduced pressure at 5 torr of degree ofvacumm for 1 hour. The thus obtained dried granules contained 3.1% ofwater (measured by the method according to Reference Example 4). Thedried granules were subjected to sizing by passing to a sieve of 850 μm.

[0408] About 1% by weight of magnesium stearate was added to the sizedgranules and mixed, then the granules were supplied to a tablet machine(Rotary single tablet press, Model VIRGO: manufactured by KIKUSUISEISAKUSHO CO., LTD.), and there were obtained tablets, each having 190mg of weight.

Example 18

[0409] a) Preparation of 30 mg Tablets Containing Type B Crystals ofAripiprazole Anhydride

[0410] Aripiprazole anhydride (type B crystals) (4,500 g), lactose(17,100 g), corn starch (3,000 g) and crystalline cellulose (3,000 g)were charged in a fluidized bed granulating dryer (NEW-MARUMERIZERModel: NQ-500, manufactured by FUJI PAUDAL CO., LTD.), and thesegranulating ingredients were mixed by fluidizing for about 3 minuteswith an inlet air temperature at 70° C., air flow rate of 10-15 m³/min.Further, the granulating ingredients were continued fluidizing under thesame condition, and were sprayed with about 12,000 g of 5% aqueoussolution of hydroxypropyl celulose to obtain wet granules. The wetgranules were dried under inlet air at temperature of 85° C., for about30 minutes. The obtained dried granules contained 3.6% of water(measured by the method according to Reference Example 4). (Yield: 96%).The dried granules were sized by passing to a mill (FIOLE F-0:manufactured by TOKUJU CORPORATION).

[0411] About 1% by weight of magnesium stearate was added to the sizedgranules and mixed, then the granules were supplied to a tablet machine(a Rotary single tablet press, VIRGO: manufactured by KIKUSUI SEISAKUSHOCO., LTD.), and there were obtained tablets, each having 190 mg ofweight.

[0412] b) The tablets (5 kg) obtained in Example 18-a) were charged in afan dryer (AQUA COATER AQC-48T, manufactured by FREUND INDUSTRIAL CO.,LTD.), and dried under inlet air at temperature of 90° C., air flow rateof 2 m³/min for 6 hours. The obtained dried granules contained 3.3% ofwater (measured by the method according to Reference Example 4).

[0413] c) The dreid tablets (3 kg) obtained in Example 18-a) werecharged in a vacuum dryer (vacuum granulating dryer, VG-50: manufacturedby KIKUSUI SEISAKUSHO CO., LTD.), and dried at 80° C. of a jackettemperature, under reduced pressure of 5 torr of degree of vacumm for 4hours. The obtained dried tablets contained 2.7% of water (measured bythe method according to Reference Example 4).

Example 19

[0414] a) By the procedures similar to those of Example 18-a), therewere obtained tablets (containing type I crystals of aripiprazoleanhydride obtained in Reference Example 2), each having 190 mg ofweight,

[0415] b) The tablets were dried by the procedures similar to those ofExample 18-b), except that air inlet temperature was 100° C. and driedfor 1 hour.

[0416] c) The tablets were dried by the procedures similar to those ofExample 18-b), except that inlet air temperature was 100° C. and driedfor 3 hours.

Example 20

[0417] By the procedures similar to those of Example 18-a), there wereobtained tablets, each having 190 mg of weight, containing type Ccrystals of aripiprazole anhydride.

Example 21

[0418] By the procedures similar to those of Example 18-a), there wereobtained tablets, each having 190 mg of weight, containing type Dcrystals of aripiprazole anhydride.

Example 22

[0419] a) Aripiprzole hydrate crystals (156 g) obtained in ReferenceExample 3, lactose (570 g), corn starch (100 g) and crystallinecellulose (100 g) were charged in a fluidized bed granulating dryer(NEW-MARUMERIZER, NQ-160: manufactured by FUJI POWDAL CO., LTD.), andthese granulating ingredients were mixed under fluidizing for about 3minutes with an inlet air temperature at 60° C., air flow rate of 1.0 to1.5 m³/min, and rotating disc with rotary speed of 400 rpm. Further, thegranulating ingredients were continued fluidizing under the samecondition, and sprayed about 500 g of 4% aqueous solution ofhydroxypropyl celulose to obtain wet granules. The inlet air temperaturewas elevated up to 85° C., and dried until the temperature of theproduct was reatched to 46° C. The obtained dried granules were sized bypassing to a sieve of 850 μm. The dried granules contained 4.37% ofwater (measured by the method according to Reference Example 4).

[0420] b) The dried granules (200 g) obtained in Example 22-a) werecharged in a fluidized bed dryer (multiplex, MP-01: manufactured byPOWREX CORPORATION), and dried at 85° C. of inlet air temperature, airflow rate of 0.5 m³/min for 2 hours. The dried granules contained 3.50%of water (measured by the method according to Reference Example 4).

[0421] c) The dried granules (100 g) obtained in Example 22-a) werecharged in a vacuum dryer (vacuum granulating dryer LCV-232:manufactured by TABAI CO., LTD.), and dried 80° C. of tray temperature,about 760 mmHg of degree of vacuum for 2 hours. The dried granules werefurther dried similarly for 6 hours. The dried granules contained 3.17%of water (the product being dried for 2 hours: measured by the methodaccording to Reference Example 4). The further dried granules contained2.88% of water (the product being dried for 6 hours: measured by themethod according to Reference Example 4).

[0422] d) About 1% by weight of magnesium stearate was added to thesized granules being obtained in Example 22-b) and mixed, then the mixedgranules were supplied to a tablet machine (Single type Tablet machineNo. 2B: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and tablettedwith punch, there were obtained tablets, each having 191 mg of weight.

[0423] e) About 1% by weight of magnesium stearate was added to thesized granules being obtained in Example 22-c) and mixed, then the mixedgranules were supplied to a tablet machine (Single type Tablet machineNo. 2B: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and tablettedwith punch, there were obtained tablets, each having 191 mg of weight.

[0424] Dissolution Test

[0425] Each tablets of the pharmaceutical solid oral preparationsobtained previously was kept, repectively under the open at 25° C./60%RH for 6 months, and at 40° C./75% RH for 1 week, then their dissolutionrates were measured by the following methods. The dissolution ratesobtained from 60 minutes after the exposure are shown in Tables 2 and 3.The dissolution rates after 60 minutes, using the tablets kept under theopen at 40° C./75% RH for 2 weeks, are shown in Tables 4 and 5. Thedissolution rates after 60 minutes, using the tablets kept under theopen condition at 40° C./75% RH for 1 week, are shown in Table 6.Dissolution test equipment: USP

[0426] Model: NTR-6100 (manufactured by TOYAMA SANGYO CO., LTD.)

[0427] Model: DT-610 (manufactured by JASCO CORPORATION)

[0428] a) Method of dissolution test of the 15 mg tablet

[0429] One tablet (containing 15 mg each of aripiprazole anhydride orhydrate) was tested by using 900 ml of acetic acid buffer solution (pH5.0) (Note: 1) as the test solution, and by rotating a paddle at 100 rpmaccording to the method of USP (United States Pharmacopoea) (Note: 2).

[0430] The test solutions obtained respectively from 10 minutes, 20minutes, 30 minutes, 45 minutes and 60 minutes after the start of testare named as T10, T20, T30, T45 and T60.

[0431] On the other hand, about 0.05 g of standard sample ofaripiprazole was weighed accurately, dissolved in ethanol (95%) so as tomake exactly 50 ml of ethanol solution. Twenty (20) ml of this ethanolsolution was taken accurately, and to prepared exactly 1000 ml of thestandard solution by adding 0.01 mol/liter of hydrochloric acid reagentsolution (Note: 3).

[0432] The test solutions and the standard solution were subjected tofiltration, respectively by using a filter having micropores of 10 to 20μm in diameters, then each of the filtrates were introduced to aspectrophotometer installed with flow cell (cell length: 10 mm), and tomeasure the absorbance of wave length at 249 nm and absorbance of wavelength at 325 nm and determined the differences between absorbances tonamed as At10, At20, At30, At45, At60 and As, respectively.

[0433] After the measurements, the test solutions of T10, T20, T30 andT45 were put back to the test vessels respectively. Further, similarprocedures were conducted to other 5 samples of the test solutions.

[0434] Dissolution rate (%) relating to the indicated amount ofaripiprazole=Amount of the standard sample of aripiprazole(mg)×At×As×9/5×20/C

[0435] wherein, At: At10, At20, At30, At45 or At60

[0436] As: standard solution

[0437] C: Indicated amount of aripiprazole (mg)

[0438] (Note: 1) Water was added to 1.97 g of acetic acid (100) and 9.15g of sodium acetate trihydrate to make 1000 ml of solution (0.1 mol/l).

[0439] (Note: 2) Paddle method

[0440] (Note: 3) Water was added to 100 ml of 0.1 mol/l hydrochloricacid (Note: 4) to make 1000 ml of solution.

[0441] (Note: 4) Water was added to 0.9 ml of hydrochloric acid to make1000 ml of solution.

[0442] b) Method of dissolution test of the 30 mg tablet

[0443] One tablet each of the pharmaceutical solid oral preparations(containing 30 mg each of aripiprazole anhydride or hydrate) was testedby using 900 ml of acetic acid buffer solution (pH 4.5) (Note: 5) as thetest solution, and to conduct the test by rotating a paddle at 75 rpm inaccordance with the method of USP (United States Pharmacopoea) (Note:6).

[0444] The test solutions obtained respectively from 10 minutes, 20minutes, 30 minutes 45 minutes and 60 minutes after the start of test,were named as T10, T20, T30, T45 and T60.

[0445] On the other hand, about 0.05 g of the standard sample ofaripiprazole was weighed accurately, and dissolved in ethanol (95%) soas to made exactly 50 ml of the ethanol solution. Twenty (20) ml of theethanol solution was taken accurately, and prepared exactly 1000 ml ofthe standard solution by adding 0.01 mol/liter of hydrochloric acidreagent solution (Note: 7).

[0446] The test solutions and standard solution were subjected tofiltration, respectively by using a filter having micropores of 10 to 20μm in diameters, then each of the filtrates were introduced to aspectrophotometer in which a flow cell (cell length: 10 mm) wasinstalled, and measured the absorbance of wave length at 249 nm andabsorbance of wave length at 325 nm, and the difference between theseabsorbances were named as At10, At20, At30, At45, At60 and As,respectively.

[0447] After the measurements, the test solutions of T10, T20, T30 andT45 were put back respectively to the test vessels. Further, similarprocedures were conducted to other 5 samples of the test solutions.

[0448] Dissolution rate (%) relating to the indicated amount ofaripiprazole=Amount of the standard sample of aripiprazole(mg)×At×As×9/5×20/C

[0449] wherein, At: At10, At20, At30, At45 or At60

[0450] As: standard solution

[0451] C: Indicated amount of aripiprazole (mg)

[0452] (Note: 5) Water was added to 1.91 g of acetic acid (100) and 2.99g of sodium acetate-trihydrate to made 1000 ml of solution (0.05 mol/l).

[0453] (Note: 6) Paddle method

[0454] (Note: 7) Water is added to 100 ml of 0.1 mol/l hydrochloric acid(Note: 8) to made 1000 ml of solution.

[0455] (Note: 8) Water was added to 0.9 ml of hydrochloric acid to make1000 ml of solution. TABLE 2 Open at 25° C./60% RH Open at 40° C./75% RHAfter After Samples used Initial 6 months Initial 1 week Tablet (15 mg)83.4% 44.3% 83.4% 44.1% of Reference Example 4 Tablet (15 mg) 90.1%61.9% 90.1% 65.2% of Reference Example 5

[0456] TABLE 3 Open at 25° C./60% RH Open at 40° C./75% RH After AfterSamples used Initial 6 months Initial 1 week Tablet (30 mg) 96.7% 77.1%96.7% 75.9% of Example 18-a) Tablet (30 mg) 96.5% 93.6% 95.0% 92.2% ofExample 17-b) Tablet (30 mg) 97.0% 96.3% 94.7% 94.8% of Example 17-c)Tablet (30 mg) 97.2% 95.3% 97.2% 97.8% of Reference Example 18-b) Tablet(30 mg) 97.8% 96.3% 97.8% 96.9% of Reference Example 18-c)

[0457] TABLE 4 Samples used Initial After 2 weeks Samples used Tablet89.8% 66.9% (30 mg) of Example 19-a) Tablet (30 mg) of — 79.8% Example19-b) Tablet (30 mg) of — 85.9% Example 19-c)

[0458] TABLE 5 Samples used Initial After 2 weeks Tablet (30 of 94.8%94.7% Example 18-a) Tablet (30 mg) of 93.7% 93.1% Example 20 Tablet (30mg) of 94.8% 90.9% Example 21

[0459] TABLE 6 Samples used Initial After 1 weeks Tablet (30 mg) of96.5% 84.5% Example 22-d) Tablet (30 mg) of 92.5% 74.4% Example 22-e)(dreid for 2 hours) Tablet (30 mg) of 96.2% 83.4% Example 22-e) (dreidfor 6 hours)

[0460] (Note: Dissolution tests in Table 5 were conducted similarly tothe procedures in the above-mentioned “b) Method of dissolution test ofthe 30 mg tablet” except that by using 900 ml of acetic acid buffersolution (pH 4.0) as the test solution, and by rotating a paddle at 50rpm.

[0461] As can be seen clearly from the data shown in Table 2, incomparison with the 15 mg tablet containing conventional aripiprazoleanhydride crystals (Reference Example 4), the 15 mg tablet containingtype B crystals of aripiprazole anhydride (Reference Example 5) had thedissolution rate to maintain maximum drug concentration (Cmax), at pH5.0 after 60 minutes, even though such tablet was kept under the open at25° C./60% RH for 6 months and under the open at 40° C./75% RH for 1week.

[0462] As can be seen clearly from the data shown in Table 3, eventhough 30 mg tablets (Examples 17-b) and 17-c)) prepared from twicedried granules of type B crystals of aripiprazole anhydride, and 30 mgtablets (Examples 18-b) and 18-c)) prepared from further driedpharmaceutical solid oral preparation containing type B crystals ofaripiprazole anhydride were subjected to keep under the open at 25°C./60% RH for 6 months or 40° C./75% RH for 1 week, the dissolutionrates of these tablets obtained 60 minutes after the test at pH 4.5 werenot substantially lowered.

[0463] As can be seen clearly from the data shown in Table 4, when 30 mgtablets (Examples 19-a), 19-b) and 19-c)) containing conventionalaripiprazole anhydride crystals were further dried and subjected to keepunder open at 40° C./75% RH for 2 weeks, then the dissolution rates ofthe tablets obtained 60 minutes after the test at pH 4.5 were thedissolution rates to maintain maximum drug concentration (Cmax).

[0464] As can be seen clearly from the data shown in Table 5, when 30 mgtablet (Example 18-a)) containing type B crystals of aripiprazoleanhydride, 30 mg tablet (Example 20) containing type C crystals ofaripiprazole anhydride and 30 mg tablet (Example 21) containing type Dcrystals of aripirazole anhydride were subjected to keep under open at40° C./75% RH for 2 weeks, then the dissolution rates of the tabletsobtained 60 minutes after the test at pH 4.0 were not substantiallylowered.

[0465] As can be seen clearly from the data shown in Table 6, when 30 mgtablets (Examples 22-d) and 22-e)) prepared from granules ofconventional aripiprazole hydrate being twice dried, and subjected tokeep under open at 40° C./75% RH for 1 week, then the dissolution ratesof the tablets obtained 60 minutes after the test at pH 4.5 were thedissolution rates to maintain maximum drug concentration (Cmax). SamplePreparation 1 Aripiprazole anhydride crystals B  5 mg Starch 131 mgMagnesium stearate  4 mg Lactose  60 mg Total 200 mg

[0466] Tablets containing the above ingredients in each tablet wereprepared by formulation methods known to one skilled in the art ofpharmaceutical formulation. Sample Preparation 2 Type C crystals ofaripiprazole anhydride  5 mg Starch 131 mg Magnesium stearate  4 mgLactose  60 mg Total 200 mg

[0467] In accordance with an ordinary method, tablet preparation,containing the above-mentioned ingredients per 1 tablet was prepared.Sample Preparation 3 Type D crystals of aripiprazole anhydride  5 mgStarch 131 mg Magnesium stearate  4 mg Lactose  60 mg Total 200 mg

[0468] In accordance with an ordinary method, tablet preparation,containing the above-mentioned ingredients per 1 tablet was prepared.Sample Preparation 4 Type E crystals of aripiprazole anhydride  5 mgStarch 131 mg Magnesium stearate  4 mg Lactose  60 mg Total 200 mg

[0469] In accordance with an ordinary method, tablet preparation,containing the above-mentioned ingredients per 1 tablet was prepared.Sample Preparation 5 Type F crystals of aripiprazole anhydride  5 mgStarch 131 mg Magnesium stearate  4 mg Lactose  60 mg Total 200 mg

[0470] In accordance with an ordinary method, tablet preparation,containing the above-mentioned ingredients per 1 tablet was prepared.Sample Preparation 6 Type G crystals of aripiprazole anhydride  5 mgStarch 131 mg Magnesium stearate  4 mg Lactose  60 mg Total 200 mg

[0471] In accordance with an ordinary method, tablet preparation,containing the above-mentioned ingredients per 1 tablet was prepared.

FORMULATION EXAMPLE

[0472] The following examples used aripiprazole drug substance made byfirst milling or pulverizing the conventional hydrate of aripiprazoleand then heating it to form the anhydrous form (anhydride B).

Formulation Example 1

[0473] Flash-melt tablets were prepared as follows:

[0474] Intragranulation: Mg. per Ingredient Percent w/w tablet Xylitol(300) Xylisorb 26 52 Avicel ® PH 102 12 24 Calcium Silicate 43.35 86.7Crospovidone 3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5Total weight 92.75 185.5

[0475] The ingredients except for the magnesium stearate were blended ina commercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was then added and the mixtureblended for an additional three minutes. The blended formulation wascompacted at a pressure of 30-35 kgF/cm² in a commercial compactorequipped with an orifice such that the compacts therefrom are in theform of ribbons. The ribbons were passed through a 30 mesh (600 microns)screen to form stable granules of about 150 to 400 microns.

[0476] Extragranulation Ingredients: Mg. per Ingredient Percent w/wtablet Intragranulation 92.75 185.5 Avicel ® PH 200 3 6 Crospovicione 48 Magnesium stearate 0.25 0.5 Total weight 100.0 200

[0477] The intragranulation was placed in the blender and the Avicel® PH200 and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.3 kP (3.5 SCU) and disintegrated in10 seconds in 5 ml of water. The final blend formulation demonstratedexcellent flow and was free of other problems such as chipping, cappingand sticking. It has been found that utilizing Avicel® PH 102 for theintragranulation and Avicel® PH 200 for the extragranulation ingredientenhanced the quality of the resultant tablets.

Formulation Example 2

[0478] Flash-melt tablets containing a combination of two grades ofcalcium silicate were prepared as follows:

[0479] Intragranulation: Mg. per Ingredient Percent w/w tablet Xylitol(300) Xylisorb 26 52 Avicel ® PH 102 12 24 Calcium Silicate(crystalline, alpha 33.35 66.7 triclinic) Hubersorb 600 NF 10 20(amorphous calcium silicate) Crospovidone 3 6 Amorphous silica 2 4Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K2 4 Magnesium stearate 0.25 0.5 Total weight 92.75 185.5

[0480] The ingredients except for the magnesium stearate were blended ina commercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofFormulation Example 1.

[0481] Extragranulation Ingredients: Mg. per Ingredient Percent w/wtablet Intragranulation 92.75 185.5 Avicel ® PH 200 3 6 Crospovidone 4 8Magnesium stearate 0.25 0.5 Total weight 100 200

[0482] The intragranulation was placed in the blender and the Avicel® PH200 and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.0 kP (3.1 SCU) and disintegrated in10 seconds in 5 ml of water.

Formulation Example 3

[0483] Flash-melt tablets containing aripiprazole, an antischizophrenicdrug, were prepared as follows:

[0484] Intragranulation Mg. per Ingredient Percent w/w tabletAripiprazole 15 30 Xylitol (300) Xylisorb 25 50 Avicel ® PH 102 6 12Calcium Silicate 37 74 Crospovidone 3 6 Amorphous silica 2 4 Aspartame 24 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4Magnesium stearate 0.25 0.5 Total weight 94.4 188.8

[0485] The ingredients except for the magnesium stearate were blended ina commercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofFormulation Example 1.

[0486] Extragranulation Ingredients: Mg. per Ingredient Percent w/wtablet Intragranulation 94.4 188.8 Avicel ® PH 200 1.1 2.2 Crospovidone4 8 Magnesium stearate 0.5 1 Total weight 100 200

[0487] The intragranulation was placed in the blender and the Avicel® PH200 and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.0 kP (3.1 SCU) and disintegrated in10 seconds in 5 ml of water.

Formulation Example 4

[0488] Flash-melt tablets containing aripiprazole were prepared asfollows:

[0489] Intragranulation: Mg. per Ingredient Percent w/w tabletAripiprazole 0.5 1 Xylitol (300) Xylisorb 27 54 Avicel ® PH 102 12 24Calcium Silicate 42 84 Crospovidone 3 6 Amorphous silica 2 4 Aspartame 24 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4Magnesium stearate 0.25 0.5 Total weight 92.9 185.8

[0490] The ingredients except for the magnesium stearate were blended ina commercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofFormulation Example 1.

[0491] Extragranulation Ingredients: Mg. per Ingredient Percent w/wtablet Intragranulation 92.9 185.8 Avicel ® PH 200 2.6 5.2 Crospovidone4 8 Magnesium stearate 0.5 1 Total weight 100 200

[0492] The intragranulation was placed in the blender and the Avicel® PH200 and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.3 kP (3.5 SCU) and disintegrated in10 seconds in 5 ml of water.

1. Hydrate A of aripiprazole wherein said Hydrate has a powder x-raydiffraction spectrum which is substantially the same as the followingpowder x-ray diffraction spectrum shown in FIG.
 3. 2. Hydrate A ofaripiprazole wherein said Hydrate has powder x-ray diffractioncharacteristic peaks at 2θ=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5° and24.8°.
 3. Hydrate A of aripiprazole wherein said Hydrate has particularinfrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187,963 and 784 cm⁻¹ on the IR (KBr) spectrum.
 4. Hydrate A of aripiprazolewherein said Hydrate has an endothermic curve which is substantially thesame as the thermogravimetric/differential thermal analysis (heatingrate 5° C./min) endothermic curve shown below shown in FIG.
 1. 5.Hydrate A of aripiprazole wherein said Hydrate has a mean particle sizeof 50 μm or less.
 6. Hydrate A of aripiprazole wherein said Hydrate hasa mean particle size range of 36 to 14 μm.
 7. Hydrate A of aripiprazolewherein said Hydrate has a powder x-ray diffraction spectrum which issubstantially the same as the following powder x-ray diffractionspectrum shown in FIG. 3; particular infrared absorption bands at 2951,2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr)spectrum; an endothermic curve which is substantially the same as thethermogravimetric/differential thermal analysis (heating rate 5° C./min)endothermic curve shown below shown in FIG. 1; and a mean particle sizeof 50 μm or less.
 8. A process for the preparation of Hydrate A whereinsaid process comprises milling Conventional Hydrate to a mean particlesize of 50 μm or less.
 9. A process according to claim 8, wherein saidmilling is performed by an atomizer using a rotational speed of5000-15000 rpm for the main axis, a feed rotation of 10-30 rpm and ascreen hole size of 1-5 mm.
 10. The Hydrate A according to claim 8 madeby a process comprising milling Conventional Hydrate to a mean particlesize of 50 μm or less.
 11. The Hydrate A according to claim 8 made by aprocess comprising milling Conventional Hydrate to a mean particle sizeof 50 μm or less wherein said milling is performed by an atomizer usinga rotational speed of 5000-15000 rpm for the main axis, a feed rotationof 10-30 rpm and a screen hole size of 1-5 mm.
 12. Aripiprazole drugsubstance of low hygroscopicity wherein said low hygroscopicity is amoisture content of 0.40% or less after placing said drug substance for24 hours in a dessicator maintained at a temperature of 60° C. and ahumidity level of 100%.
 13. Aripiprazole Anhydride Crystals B having lowhygroscopicity wherein said low hygroscopicity is a moisture content of0.40% or less after placing said drug substance for 24 hours in adessicator maintained at a temperature of 60° C. and a humidity level of100%.
 14. Aripiprazole drug substance of low hygroscopicity wherein saidlow hygroscopicity is a moisture content of 0.10% or less after placingsaid drug substance for 24 hours in a dessicator maintained at atemperature of 60° C. and a humidity level of 100%.
 15. AripiprazoleAnhydride Crystals B having low hygroscopicity wherein said lowhygroscopicity is a moisture content of 0.10% or less after placing saiddrug substance for 24 hours in a dessicator maintained at a temperatureof 60° C. and a humidity level of 100%.
 16. Aripiprazole AnhydrideCrystals B having a powder x-ray diffraction spectrum which issubstantially the same as the following powder x-ray diffractionspectrum shown in FIG.
 5. 17. Aripiprazole Anhydride Crystals B having apowder x-ray diffraction spectrum having characteristic peaks at2θ=11.0°, 16.6°, 19.3°, 20.3° and 22.1°.
 18. Aripiprazole AnhydrideCrystals B having a particular infrared absorption bands at 2945, 2812,1678, 1627, 1448, 1377, 1173, 960 and 779 cm⁻¹ on the IR (KBr) spectrum.19. Aripiprazole Anhydride Crystals B exhibiting an endothermic peaknear about 141.5° C. in thermogravimetric/differential thermal analysis(heating rate 5° C./min).
 20. Aripiprazole Anhydride Crystals Bexhibiting an endothermic peak near about 140.7° C. in differentialscanning calorimetry (heating rate 5° C./min).
 21. AripiprazoleAnhydride Crystals B wherein said Crystals will not substantiallyconvert to a hydrous form of aripiprazole when properly stored under arelative humidity (RH) of 60% and at a temperature of 25° C., even foran extended period being not less than 4 years.
 22. AripiprazoleAnhydride Crystal B wherein said crystals has a mean particle size of 50μm or less.
 23. Aripiprazole Anhydride Crystal B wherein said crystalshas a mean particle size of 30 μm or less.
 24. Aripiprazole AnhydrideCrystals B having all physicochemical properties defined in claims 16and 18 to
 22. 25. Aripiprazole Anhydride Crystals B having allphysicochemical properties defined in claims 17 to
 22. 26. AripiprazoleAnhydride Crystals B having all physicochemical properties defined inclaims 13, 16, 18 to 20 and
 22. 27. Aripiprazole Anhydride Crystals Bhaving all physicochemical properties defined in claims 15, 16, 18 to 20and
 22. 28. Aripiprazole Anhydride Crystals B having all physicochemicalproperties defined in claims 13, 17 to 20 and
 22. 29. AripiprazoleAnhydride Crystals B having all physicochemical properties defined inclaims 15, 17 to 20 and
 22. 30. A process for the preparation ofAripiprazole Anhydride Crystals B wherein said process comprises heatingAripiprazole Hydrate A.
 31. A process for the preparation ofAripiprazole Anhydride Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 90-125° C. for about 3-50 hours.
 32. A processfor the preparation of Aripiprazole Anhydride Crystals B wherein saidprocess comprises heating Aripiprazole Hydrate A at 100° C. for about 18hours.
 33. A process for the preparation of Aripiprazole AnhydrideCrystals B wherein said process comprises heating Aripiprazole Hydrate Aat 100° C. for about 24 hours.
 34. A process for the preparation ofAripiprazole Anhydride Crystals B wherein said process comprises heatingAripiprazole Hydrate A at 120° C. for about 3 hours.
 35. A process forthe preparation of Aripiprazole Anhydride Crystals B wherein saidprocess comprises heating Aripiprazole Hydrate A for about 18 hours at100° C. followed by additional heating for about 3 hours at 120° C. 36.The Aripiprazole Anhydride Crystals B according to any one of claims24-29 made by a process comprising heating Aripiprazole Hydrate A forabout 18 hours at 100° C. followed by additional heating for about 3hours at 120° C.
 37. The Aripiprazole Anhydride Crystals B according toany one of claims 24-29 formulated with one or more pharmaceuticallyacceptable carriers.
 38. The Aripiprazole Anhydride Crystals B accordingto any one of claims 24-29 formulated with one or more pharmaceuticallyacceptable carriers to form a solid oral tablet.
 39. The AripiprazoleAnhydride Crystals B according to any one of claims 24-29 formulatedwith one or more pharmaceutically acceptable carriers to form an oralflashmelt tablet.
 40. A process for the pharmaceutical solid oralpreparation comprising Aripiprazole Anhydride Crystals B defined inclaim 26 and one or more pharmaceutically acceptable carriers, whereinsaid process comprises heating Aripiprazole Hydrate A defined in claim7.
 41. A process for the pharmaceutical solid oral preparationcomprising Aripiprazole Anhydride Crystals B defined in claim 26 and oneor more pharmaceutically acceptable carriers, wherein said processcomprises heating Aripiprazole Hydrate A defined in claim 7 at 90-125°C. for about 3-50 hours.
 42. A process for the pharmaceutical solid oralpreparation comprising Aripiprazole Anhydride Crystals B defined inclaim 27 and one or more pharmaceutically acceptable carriers, whereinsaid process comprises heating Aripiprazole Hydrate A defined in claim7.
 43. A process for the pharmaceutical solid oral preparationcomprising Aripiprazole Anhydride Crystals B defined in claim 27 and oneor more pharmaceutically acceptable carriers, wherein said processcomprises heating Aripiprazole Hydrate A defined in claim 7 at 90-125°C. for about 3-50 hours.
 44. A process for the pharmaceutical solid oralpreparation comprising Aripiprazole Anhydride Crystals B defined inclaim 28 and one or more pharmaceutically acceptable carriers, whereinsaid process comprises heating Aripiprazole Hydrate A defined in claim7.
 45. A process for the pharmaceutical solid oral preparationcomprising Aripiprazole Anhydride Crystals B defined in claim 28 and oneor more pharmaceutically acceptable carriers, wherein said processcomprises heating Aripiprazole Hydrate A defined in claim 7 at 90-125°C. for about 3-50 hours.
 46. A process for the pharmaceutical solid oralpreparation comprising Aripiprazole Anhydride Crystals B defined inclaim 29 and one or more pharmaceutically acceptable carriers, whereinsaid process comprises heating Aripiprazole Hydrate A defined in claim7.
 47. A process for the pharmaceutical solid oral preparationcomprising Aripiprazole Anhydride Crystals B defined in claim 29 and oneor more pharmaceutically acceptable carriers, wherein said processcomprises heating Aripiprazole Hydrate A defined in claim 7 at 90-125°C. for about 3-50 hours.
 48. Aripiprazole Anhydride Crystals B whereinsaid Crystals will not substantially convert to a hydrous form ofaripiprazole when properly stored under a relative humidity (RH) of 60%and at a temperature of 25° C., even for an extended period being notless than 1 year.
 49. Aripiprazole Anhydride Crystals B wherein saidCrystals will not substantially convert to a hydrous form ofaripiprazole when properly stored under a relative humidity (RH) of 75%and at a temperature of 40° C., even for an extended period being notless than 0.5 year.
 50. Aripiprazole Anhydride Crystals B having allphysicochemical properties defined in claims 16, 18 to 20, 22 and 48.51. Aripiprazole Anhydride Crystals B having all physicochemicalproperties defined in claims 17 to 20, 22 and
 48. 52. AripiprazoleAnhydride Crystals B having all physicochemical properties defined inclaims 16, 18 to 20, 22 and
 49. 53. Aripiprazole Anhydride Crystals Bhaving all physicochemical properties defined in claims 17 to 20, 22 and49.
 54. The Aripiprazole Anhydride Crystals B according to any one ofclaims 50-53 formulated with one or more pharmaceutically acceptablecarriers.
 55. The Aripiprazole Anhydride Crystals B according to any oneof claims 50-53 formulated with one or more pharmaceutically acceptablecarriers to form a solid oral tablet.
 56. The Aripiprazole AnhydrideCrystals B according to any one of claims 50-53 formulated with one ormore pharmaceutically acceptable carriers to form an oral flashmelttablet.
 57. The use of aripiprazole anhydride crystals B for thetreatment of central system disorder.
 58. The use of aripiprazoleanhydride crystals B for the treatment of schizophrenia.
 59. The use ofaripiprazole anhydride crystals B for the treatment of bipolar disorder.60. The use of aripiprazole anhydride crystals B for the treatment ofintractable (drug-resistent, chronic) schizophrenia with cognitiveimpairment or intractable (drug-resistant, chronic) schizophreniawithout cognitive impairment.
 61. The use of aripiprazole anhydridecrystals B for the treatment of autism, Down's syndrome or attentiondeficit hyperactivity disorder (ADHD).
 62. The use of aripiprazoleanhydride crystals B for the treatment of Alzheimer's disease,Parkinson's disease or other neurodegenerative diseases.
 63. The use ofaripiprazole anhydride crystals B for the treatment of panic, obsessivecompulsive disorder (OCD), sleep disorders, sexual dysfunction, alcoholand drug dependency, vomiting, motion sickness, obesity, miparticleeheadache or cognitive impairment.
 64. The use of aripiprazole anhydridecrystals B for the treatment of anxiety, depression or mania.
 65. Theuse of aripiprazole anhydride crystals B to prepare a medicament totreat or prevent schizophrenia and the symptoms associated withschizophrenia.
 66. A drug for treating schizophrenia or symptomsassociated with schizophrenia, which comprises aripiprazole anhydridecrystals B in an amount effective to treat schizophrenia or the symptomsthereof, in admixture with a pharmaceutically acceptable diluent. 67.The drug as claimed in claim 66, which is contained in a commercialpackage carrying instructions that the drug should be used for treatingschizophrenia, or symptoms thereof.
 68. A process for the preparation ofgranules, characterized by wet granulating the Aripiprazole AnhydrideCrystals B defined in claim 26, drying the obtained granules at 70 to100° C. and sizing it, then drying the sized granules at 70 to 100° C.again.
 69. A process for the preparation of granules, characterized bywet granulating the Aripiprazole Anhydride Crystals B defined in claim27, drying the obtained granules at 70 to 100° C. and sizing it, thendrying the sized granules at 70 to 100° C. again.
 70. A process for thepreparation of granules, characterized by wet granulating theAripiprazole Anhydride Crystals B defined in claim 28, drying theobtained granules at 70 to 100° C. and sizing it, then drying the sizedgranules at 70 to 100° C. again.
 71. A process for the preparation ofgranules, characterized by wet granulating the Aripiprazole AnhydrideCrystals B defined in claim 29, drying the obtained granules at 70 to100° C. and sizing it, then drying the sized granules at 70 to 100° C.again.
 72. A process for the pharmaceutical solid oral preparation,characterized by drying a pharmaceutical solid oral preparationcomprising the Aripiprazole Anhydride Crystals B defined in claim 26 andone or more pharmaceutically acceptable carriers at 70 to 100° C.
 73. Aprocess for the pharmaceutical solid oral preparation, characterized bydrying a pharmaceutical solid oral preparation comprising theAripiprazole Anhydride Crystals B defined in claim 27 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 74. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals B defined in claim 28 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 75. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals B defined in claim 29 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 76. Thepharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals B defined in claim 26 and one or morepharmaceutically acceptable carriers, wherein said pharmaceutical solidoral preparation has at least one dissolution rate selected from thegroup consisting 60% or more at pH 4.5 after 30 minutes, 70% or more atpH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes. 77.The pharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals B defined in claim 27 and one or morepharmaceutically acceptable carriers, wherein said pharmaceutical solidoral preparation has at least one dissolution rate selected from thegroup consisting 60% or more at pH 4.5 after 30 minutes, 70% or more atpH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes. 78.The pharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals B defined in claim 28 and one or morepharmaceutically acceptable carriers, wherein said pharmaceutical solidoral preparation has at least one dissolution rate selected from thegroup consisting 60% or more at pH 4.5 after 30 minutes, 70% or more atpH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes. 79.The pharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals B defined in claim 29 and one or morepharmaceutically acceptable carriers, wherein said pharmaceutical solidoral preparation has at least one dissolution rate selected from thegroup consisting 60% or more at pH 4.5 after 30 minutes, 70% or more atpH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes. 80.Aripiprazole Anhydride Crystals C having a powder X-ray diffractionspectrum shown in FIG.
 10. 81. Aripiprazole Anhydride Crystals C havinga powder X-ray diffraction spectrum having characteristics peaks at2θ=12.6°, 13.7°, 15.4°, 18.1°, 19.0°, 20.6°, 23.5° and 26.4°. 82.Aripiprazole Anhydride crystals C having a particular infraredabsorption bands at 2939, 2804, 1680, 1375 and 780 cm⁻¹ on the IR (Kbr)spectrum.
 83. Aripiprazole Anhydride crystals C exhibitng an endothermicpeak near about 150.2° C. in thermogravimetric/differential thermalanalysis (heating rate 5° C./min).
 84. Aripiprazole Anhydride crystals Chaving a solid ¹³C-NMR spectrum having characteristic peaks at 32.8 ppm,60.8 ppm, 74.9 ppm, 104.9 ppm, 152.2 ppm and 175.2 ppm.
 85. AripiprazoleAnhydride crystals C having all physicochemical properties defined inclaims 80, 82 to
 84. 86. Aripiprazole Anhydride crystals C having allphysicochemical properties defined in claims 81 to
 84. 87. AripiprazoleAnhydride crystals D having a powder x-ray diffraction spectrum shown inFIG.
 15. 88. Aripiprazole Anhydride crystals D having a powder x-raydiffraction spectrum having characteristic peaks at 2θ=8.7°, 11.6°,16.3°, 17.7°, 18.6°, 20.3°, 23.4° and 25.0°.
 89. Aripiprazole Anhydridecrystals D having a particular infrared absorption bands at 2946, 1681,1375, 1273, 1175 and 862 cm⁻¹ on the IR (Kbr) spectrum.
 90. AripiprazoleAnhydride crystals D exhibiting an endothermic peak near about 136.8° C.and 141.6° C. in thermogravimetric/differential thermal analysis(heating rate 5° C./min).
 91. Aripiprazole Anhydride crystals D having asolid ¹³C-NMR spectrum having characteristic peaks at 32.1 ppm, 62.2ppm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.4 ppm, and 174.1 ppm. 92.Aripiprazole Anhydride crystals D having all physicochemical propertiesdefined in claims 87, 89 to
 91. 93. Aripiprazole Anhydride crystals Dhaving all physicochemical properties defined in claims 88 to
 91. 94.Aripiprazole Anhydride crystals E having a powder x-ray diffractionspectrum shown in FIG.
 20. 95. Aripiprazole Anhydride crystals E havinga powder x-ray diffraction spectrum having characteristic peaks at2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5° and 24.0°.
 96. AripiprazoleAnhydride crystals E having a particular infrared absorption bands at2943, 2817, 1686, 1377, 1202, 969 and 774 cm⁻¹ on the IR (Kbr) spectrum.97. Aripiprazole Anhydride crystals E exhibiting an endothermic peaknear about 146.5° C. in thermogravimetric/differential thermal analysis(heating rate 5° C./min).
 98. Aripiprazole Anhydride crystals E havingall physicochemical properties defined in claims 94, 96 to
 97. 99.Aripiprazole Anhydride crystals E having all physicochemical propertiesdefined in claims 95 to
 97. 100. Aripiprazole Anhydride crystals Fhaving a powder x-ray diffraction spectrum shown in FIG.
 24. 101.Aripiprazole Anhydride crystals F having a powder x-ray diffractionspectrum having characteristic peaks at 2θ=11.3°, 13.3°, 15.4°, 22.8°,25.2° and 26.9°.
 102. Aripiprazole Anhydride crystals F having aparticular infrared absorption bands at 2940, 2815, 1679, 1383, 1273,1177, 1035, 963 and 790 cm⁻¹ on the IR (Kbr) spectrum.
 103. AripiprazoleAnhydride crystals F exhibiting an endothermic peak near about 137.5° C.and 149.8° C. in thermogravimetric/differential thermal analysis (hatingrate 5° C./min).
 104. Aripiprazole Anhydride crystals F having allphysicochemical properties defined in claims 100, 102 to
 103. 105.Aripiprazole Anhydride crystals F having all physicochemical propertiesdefined in claims 101 to
 103. 106. Aripiprazole Anhydride crystals Ghaving a powder x-ray diffraction spectrum shown in FIG.
 28. 107.Aripiprazole Anhydride crystals G having a powder x-ray diffractionspectrum having characteristic peaks at 2θ=10.1°, 12.8°, 15.2°, 17.0°,17.5°, 19.1°, 20.1°, 21.2°, 22.4°, 23.3°, 24.5° and 25.8°. 108.Aripiprazole Anhydride crystals G having a particular infraredabsorption bands at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787 cm⁻¹on the IR (Kbr) spectrum.
 109. Aripiprazole Anhydride crystals Gexhibiting an endothermic peak near about 141.0° C. and an exothermicpeak around 122.7° C. in thermogravimetric/differential thermal analysis(heating rate 5° C./min).
 110. Aripiprazole Anhydride crystals G havingall physicochemical properties defined in claims 106, 108 to
 109. 111.Aripiprazole Anhydride crystals G having all physicochemical propertiesdefined in claims 107 to
 109. 112. A process for preparing aripiprazoleanhydride crystals C according to claim 85 or 86, characterized byheating aripiprazole anhydride crystals at a temperature higher than140° C. and lower than 150° C.
 113. A process for preparing aripiprazoleanhydride crystals D according to claim 92 or 93, characterized byrecrystallizing it from toluene.
 114. A process for preparingaripiprazole anhydride crystals E according to claim 98 or 99,characterized by heating and dissolving aripiprazole anhydride crystalsin acetonitrile, then cooling it.
 115. A process for preparingaripiprazole anhydride crystals F according to claim 104 or 105,characterized by heating a suspension of aripiprazole anhydride inacetone.
 116. A process for preparing aripiprazole anhydride crystals Gaccording to claim 110 or 111, characterized by leaving to standaripiprazole anhydride glassy state in a sealed vessel at roomtemperature for at least 2 weeks.
 117. A pharmaceutical compositioncomprising at least one aripiprazole anhydride crystals selected fromthe group consisting of the aripiprazole anhydride crystals C accordingto claim 85, the aripiprazole anhydride crystals D according to claim92, the aripiprazole anhydride crystals E according to claim 98, thearipiprazole anhydride crystals F according to claim 104 and thearipiprazole anhydride crystals G according to claim 110, together withpharmaceutically acceptable carriers.
 118. A pharmaceutical compositioncomprising at least one aripiprazole anhydride crystals selected fromthe aripiprazole anhydride crystals C according to claim 86, thearipiprazole anhydride crystals D according to claim 93, thearipiprazole anhydride crystals E according to claim 99, thearipiprazole anhydride crystals F according to claim 105, and thearipiprazole anhydride crystals G according to claim 111, together withpharmaceutically acceptable carriers.
 119. A process for the preparationof granules, characterized by wet granulating the Aripiprazole AnhydrideCrystals C defined in claim 85, drying the obtained granules at 70 to100° C. and sizing it, then drying the sized granules at 70 to 100° C.again.
 120. A process for the preparation of granules, characterized bywet granulating the Aripiprazole Anhydride Crystals C defined in claim86, drying the obtained granules at 70 to 100° C. and sizing it, thendrying the sized granules at 70 to 100° C. again.
 121. A process for thepreparation of granules, characterized by wet granulating theAripiprazole Anhydride Crystals D defined in claim 92, drying theobtained granules at 70 to 100° C. and sizing it, then drying the sizedgranules at 70 to 100° C. again.
 122. A process for the preparation ofgranules, characterized by wet granulating the Aripiprazole AnhydrideCrystals D defined in claim 93, drying the obtained granules at 70 to100° C. and sizing it, then drying the sized granules at 70 to 100° C.again.
 123. A process for the preparation of granules, characterized bywet granulating the Aripiprazole Anhydride Crystals E defined in claim98, drying the obtained granules at 70 to 100° C. and sizing it, thendrying the sized granules at 70 to 100° C. again.
 124. A process for thepreparation of granules, characterized by wet granulating theAripiprazole Anhydride Crystals E defined in claim 99, drying theobtained granules at 70 to 100° C. and sizing it, then drying the sizedgranules at 70 to 100° C. again.
 125. A process for the preparation ofgranules, characterized by wet granulating the Aripiprazole AnhydrideCrystals F defined in claim 104, drying the obtained granules at 70 to100° C. and sizing it, then drying the sized granules at 70 to 100° C.again.
 126. A process for the preparation of granules, characterized bywet granulating the Aripiprazole Anhydride Crystals F defined in claim105, drying the obtained granules at 70 to 100° C. and sizing it, thendrying the sized granules at 70 to 100° C. again.
 127. A process for thepreparation of granules, characterized by wet granulating theAripiprazole Anhydride Crystals G defined in claim 110, drying theobtained granules at 70 to 100° C. and sizing it, then drying the sizedgranules at 70 to 100° C. again.
 128. A process for the preparation ofgranules, characterized by wet granulating the Aripiprazole AnhydrideCrystals G defined in claim 111, drying the obtained granules at 70 to100° C. and sizing it, then drying the sized granules at 70 to 100° C.again.
 129. A process for the pharmaceutical solid oral preparation,characterized by drying a pharmaceutical solid oral preparationcomprising the Aripiprazole Anhydride Crystals C defined in claim 85 andone or more pharmaceutically acceptable carriers at 70 to 100°C.
 130. Aprocess for the pharmaceutical solid oral preparation, characterized bydrying a pharmaceutical solid oral preparation comprising theAripiprazole Anhydride Crystals C defined in claim 86 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 131. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals D defined in claim 92 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 132. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals D defined in claim 93 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 133. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals E defined in claim 98 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 134. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals E defined in claim 99 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 135. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals F defined in claim 104 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 136. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals F defined in claim 105 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 137. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals G defined in claim 110 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 138. A process forthe pharmaceutical solid oral preparation, characterized by drying apharmaceutical solid oral preparation comprising the AripiprazoleAnhydride Crystals G defined in claim 111 and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 139. A process forthe preparation of granules, characterized by wet granulatingconventional Aripiprazole Anhydride Crystals, drying the obtainedgranules at 70 to 100° C. and sizing it, then drying the sized granulesat 70 to 100° C. again.
 140. A process for the pharmaceutical solid oralpreparation, characterized by drying a pharmaceutical solid oralpreparation comprising conventional Aripiprazole Anhydride Crystals andone or more pharmaceutically acceptable carriers at 70 to 100° C.
 141. Apharmaceutical solid oral preparation having at least one dissolutionrate selected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.
 142. The pharmaceutical solid oral preparationprepared by the process of claim 139, wherein said pharmaceutical solidoral preparation has at least one dissolution rate selected from thegroup consisting 60% or more at pH 4.5 after 30 minutes, 70% or more atpH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.143. The pharmaceutical solid oral preparation prepared by the processof claim 140, wherein said pharmaceutical solid oral preparation havingat least one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 144. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Cdefined in claim 85 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 145. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Cdefined in claim 86 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 146. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Ddefined in claim 92 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 147. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Ddefined in claim 93 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 148. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Edefined in claim 98 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 149. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Edefined in claim 99 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 150. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Fdefined in claim 104 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 151. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Fdefined in claim 105 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 152. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Gdefined in claim 110 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 153. The pharmaceuticalsolid oral preparation comprising the Aripiprazole Anhydride Crystals Gdefined in claim 111 and one or more pharmaceutically acceptablecarriers, wherein said pharmaceutical solid oral preparation has atleast one dissolution rate selected from the group consisting 60% ormore at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,and 55% or more at pH 5.0 after 60 minutes.
 154. A process for thepreparation of granules, characterized by wet granulating conventionalAripiprazole Hydrate Crystals, drying the obtained granules at 70 to100° C. and sizing it, then drying the sized granules at 70 to 100° C.again.
 155. A process for the pharmaceutical solid oral preparation,characterized by drying a pharmaceutical solid oral preparationcomprising conventional Aripiprazole Hydrate Crystals and one or morepharmaceutically acceptable carriers at 70 to 100° C.
 156. Thepharmaceutical solid oral preparation prepared by the process of claim154, wherein said pharmaceutical solid oral preparation has at least onedissolution rate selected from the group consisting 60% or more at pH4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% ormore at pH 5.0 after 60 minutes.
 157. The pharmaceutical solid oralpreparation prepared by the process of claim 155, wherein saidpharmaceutical solid oral preparation has at least one dissolution rateselected from the group consisting 60% or more at pH 4.5 after 30minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH5.0 after 60 minutes.